Processes for the preparation of ortho-allylated hydroxy aryl compounds

ABSTRACT

The present application describes process for preparing an ortho-allylated hydroxy aryl compounds such as compounds of Formula (I) by reacting an allylic alcohol with a hydroxy aryl compound in the presence of aluminum compound selected from alumina and aluminum alkoxides and in a non-protic solvent wherein at least one carbon atom ortho to the hydroxy group in the hydroxy aryl compound is unsubstituted. The present application also includes compounds of Formula (I).

RELATED APPLICATIONS

The present application is a divisional of co-pending U.S. patentapplication Ser. No. 17/303,462 filed on May 28, 2021 which claims thebenefit of priority of U.S. provisional patent application No.63/031,997 filed on May 29, 2020 the contents of both of which areincorporated herein by reference in their entirety.

FIELD

The present application is related to process for preparingortho-allylated hydroxy aryl compounds, in particular using alumina oraluminum alkoxides and a non-protic solvent.

BACKGROUND

The phenol (or hydroxy aryl) moiety is ubiquitous in natural productsand present in many synthetic compounds of value in medicinal chemistryand materials sciences.¹⁻³ Regiospecific ortho allylation of phenolspresents a significant synthetic challenge.⁴⁻⁶ More broadly, any form ofortho-regiospecific functionalization of phenols is a syntheticchallenge that has previously been addressed with creative syntheticmethodology solutions.⁷⁻¹⁷

Phenols undergo electrophilic aromatic substitution (EAS) reactions withgenerally poor regioselectivity between ortho- and para-positions,although enhancement of ortho-selectivity has been achieved for somesubstrates with a variety of additives including amines⁴⁵⁻⁴⁷ ammoniumsalts,⁴⁸ thioureas,⁴⁹⁻⁵¹ and Lewis acids.⁵²⁻⁵⁵ Similarly, oxidativemethods of phenol substitution also typically yield mixtures of ortho-and para-substituted products,⁵⁶ with ortho-enhancement reported in rarecases.⁵⁷⁻⁶¹ Ball and co-workers recently developed an ortho-specificarylation of unprotected phenols with boronic acids using astoichiometric bismuth reagent.⁶² Therefore, the efficient one-steportho-selective substitution unprotected phenols remains a syntheticchallenge.

SUMMARY

The Applicants have developed an efficient one step process of preparingortho-allylated hydroxy aryl compounds (e.g. ortho-allylated phenolics).More specifically, the Applicants have discovered a general new approachto the ortho-allylation of unprotected hydroxy aryl compounds (e.gphenolics) using allylic alcohols through alumina promoted allylation innon-protic, for example hydrophobic, solvents. Using various allylicalcohols and phenolics, the Applicants have shown that when using thisprocess, the allylation occurs regiospecifically with the allylationoccuring preferentially at a position ortho to the hydroxy of thehydroxy aryl compound.

The Applicants have also discovered that the ortho-allylation ofunprotected hydroxy aryl compounds with allylic alcohols can be effectedusing alumina in combination with further additives includingdehydrating agents such as magnesium sulfate. The Applicants havefurther surprisingly discovered that the ortho-allylation of unprotectedhydroxy aryl compounds with allylic alcohols can also be effected usingaluminum alkoxides such as aluminum isopropoxide,

Accordingly, the application includes a process for preparing anortho-allylated hydroxy aryl compound comprising reacting an allylicalcohol with a hydroxy aryl compound in the presence of an aluminumcompound selected from alumina and aluminum alkoxides and in anon-protic solvent to form the ortho-allylated hydroxy aryl compound,wherein at least one carbon atom ortho to the hydroxy group in thehydroxy aryl compound is unsubstituted.

In an embodiment, the application further includes a process forpreparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in presence of aluminum compound selected from alumina and aluminumalkoxides and in a non-protic solvent to form the compound of Formula(I),

-   -   wherein:    -   each R¹ is independently OH, halo, CN, NO₂ or COOH, or        independently selected from any suitable unsubstituted or        substituted alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, Z-alkyl, Z-alkenyl,        Z-alkynyl, Z-cycloalkyl, Z-heterocycloalkyl, Z-aryl, Z and        Z-heteroaryl, wherein the substituents are selected from OH,        halo, alkyl, O-alkyl, aryl, cycloalkyl, heteroaryl and        heterocycloalkyl groups, or    -   when n is greater than 1, two R¹ groups are linked together to        form an unsubstituted or substituted polycyclic ring system        having 8 or more atoms together with the phenyl ring to which        said R¹ groups are bonded, and in which one or more carbon atoms        in said polycyclic ring system is optionally replaced with a        heteromoiety selected from NR⁶, O and S; wherein the polycyclic        ring system is optionally substituted with one or more        substituents selected from ═O, OH, halo, alkyl, alkenyl,        alkynyl, O-alkyl, O-alkenyl, O-alkynyl, aryl, heteroaryl,        cycloalkyl, and heterocycloalkyl, the latter 10 groups being        optionally substituted with one or more substituents selected        from OH, alkyl, alkenyl, and O-alkyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is H;    -   R³ is selected from H and any suitable unsubstituted or        substituted alkyl; R⁴ is H, or selected from any suitable        unsubstituted or substituted alkyl; aryl, alkylenearyl,        heteroaryl, and alkyleneheteroaryl;    -   R⁵ is H, or selected from any suitable unsubstituted or        substituted alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, wherein the substituents        are selected from OH, halo, alkyl, O-alkyl, aryl, cycloalkyl,        heteroaryl and heterocycloalkyl groups; or    -   any two of R², R³, R⁴ and R⁵ are linked together to form an        unsubstituted or substituted monocyclic or polycyclic ring        system having 4 or more atoms together with the carbon atoms to        which said any two of R², R³, R⁴ and R⁵ are bonded, wherein the        monocyclic or polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo, alkyl,        alkenyl, alkynyl, O-alkyl, O-alkenyl, O-alkynyl, aryl,        heteroaryl, cycloalkyl, and heterocycloalkyl, the latter 10        groups being optionally substituted with OH, alkyl, alkenyl and        O-alkyl;    -   R⁶ and R⁷ are independently selected from H and unsubstituted or        substituted alkyl;    -   n is an integer selected from 0 to 4, and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the application further includes a process forpreparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in presence of an aluminum compound selected from alumina and aluminumalkoxides and in a hydrophobic solvent under forming of the compound ofFormula (I),

-   -   wherein:    -   each R¹ is independently selected from OH, halo, CN, NO₂, COOH,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈ cycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈ cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl, C₁₋₁₀alkenyleneC₃₋₁₈        heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl,        C₆₋₁₈aryl, C₁₋₁₆alkyleneC₆₋₁₈ aryl, C₂₋₁₆alkenyleneC₆₋₁₈ aryl,        C₂₋₁₆alkynyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyl, Z—C₂₋₁₆alkenyl,        Z—C₂₋₁₆alkynyl, Z—C₃₋₁₈ cycloalkyl,        Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈        cycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl,        Z—C₃₋₁₈heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl,        Z—C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, Z—C₆₋₁₈ aryl,        Z—C₁₋₁₆alkyleneC₆₋₁₈ aryl, Z—C₂₋₁₆alkenyleneC₆₋₁₈ aryl,        Z—C₂₋₁₆alkynyleneC₆₋₁₈ aryl, Z—C₅₋₁₈heteroaryl,        Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,        Z—C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, and        Z—C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,    -   wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        groups are optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; or    -   when n is greater than 1, two R¹ groups are linked together to        form a polycyclic ring system having 8 or more atoms together        with the phenyl ring to which said groups are bonded, and in        which one or more carbon atoms in said polycyclic ring system is        optionally replaced with a heteromoiety selected from NR⁶, O and        S, wherein the polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈        heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups being        optionally substituted with one or more substituents selected        from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is selected from H,    -   R³ is selected from H and C₁₋₆alkyl,    -   R⁴ is selected from H, C₁₋₆alkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₅₋₁₈ heteroaryl, and        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl;    -   R⁵ is selected from H, C₁₋₂₆alkyl, C₂₋₂₆alkenyl, C₂₋₂₆alkynyl,        C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈cycloalkyl,        C₃₋₁₈ heterocycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        C₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, C₆₋₁₈aryl, C₁₋₁₆alkyleneC₆₋₁₈ aryl,        C₂₋₁₆alkenyleneC₆₋₁₈aryl, C₂₋₁₆alkynyleneC₆₋₁₈aryl,        C₅₋₁₈heteroaryl, C₂₋₁₆alkyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,        wherein all cycloalkyl, heterocycloalkyl, aryl and heteroaryl        are optionally substituted with one or more substituents        selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,        C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁹        C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹, SO₃C₁₋₁₆alkyl,        SO₃C₆₋₁₆aryl, and SO₃C₅₋₁₈heteroaryl substituted with        C₁₋₁₆alkyl; or any two of R², R³, R⁴ and R⁵ are linked together        to form an unsubstituted or substituted monocyclic or polycyclic        ring system having 4 or more atoms together with the carbon        atoms to which said any two of R², R³, R⁴ and R⁵ are bonded,        wherein the monocyclic or polycyclic ring system is optionally        substituted with one or more substituents selected ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,        OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸,        C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl,        C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the        latter 4 groups being optionally substituted with one or more        substituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl,        and C₂₋₁₆alkenyl;    -   R⁶, R⁷, R⁸ and R⁹ are independently selected from H and        C₁₋₆alkyl;    -   n is an integer selected from 0 to 4, and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

The present application also includes novel compounds of Formula (I).

Other features and advantages of the present application will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating embodiments of the application, are given byway of illustration only and the scope of the claims should not belimited by these embodiments, but should be given the broadestinterpretation consistent with the description as a whole.

DETAILED DESCRIPTION I. Definitions

Unless otherwise indicated, the definitions and embodiments described inthis and other sections are intended to be applicable to all embodimentsand aspects of the present application herein described for which theyare suitable as would be understood by a person skilled in the art.

All features disclosed in the specification, including the claims,abstract, and drawings, and all the steps in any method or processdisclosed, may be combined in any combination, except combinations whereat least some of such features and/or steps are mutually exclusive. Eachfeature disclosed in the specification, including the claims, abstract,and drawings, can be replaced by alternative features serving the same,equivalent, or similar purpose, unless expressly stated otherwise.

The term “process of the application” and the like as used herein refersto a process of preparing ortho-allylated hydroxy aryl compoundsincluding compounds of Formula (I) and (I-A) as described herein.

The term “and/or” as used herein means that the listed items arepresent, or used, individually or in combination. In effect, this termmeans that “at least one of” or “one or more” of the listed items isused or present. The term “and/or” with respect to pharmaceuticallyacceptable salts and/or solvates thereof means that the compounds of theapplication exist as individual salts and hydrates, as well as acombination of, for example, a solvate of a salt of a compound of theapplication.

As used in the present application, the singular forms “a”, “an” and“the” include plural references unless the content clearly dictatesotherwise. For example, an embodiment including “a solvent” should beunderstood to present certain aspects with one solvent, or two or moreadditional solvents.

In embodiments comprising an “additional” or “second” component, such asan additional or second solvent, the second component as used herein ischemically different from the other components or first component. A“third” component is different from the other, first, and secondcomponents, and further enumerated or “additional” components aresimilarly different.

As used in this application and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “include” and “includes”) or “containing”(and any form of containing, such as “contain” and “contains”), areinclusive or open-ended and do not exclude additional, unrecitedelements or process steps.

The term “consisting” and its derivatives as used herein are intended tobe closed terms that specify the presence of the stated features,elements, components, groups, integers, and/or steps, and also excludethe presence of other unstated features, elements, components, groups,integers and/or steps.

The term “consisting essentially of”, as used herein, is intended tospecify the presence of the stated features, elements, components,groups, integers, and/or steps as well as those that do not materiallyaffect the basic and novel characteristic(s) of these features,elements, components, groups, integers, and/or steps.

The term “suitable” as used herein means that the selection of theparticular compound or conditions would depend on the specific syntheticmanipulation to be performed, the identity of the molecule(s) to betransformed and/or the specific use for the compound, but the selectionwould be well within the skill of a person trained in the art. Allprocess/method steps described herein are to be conducted underconditions sufficient to provide the product shown. A person skilled inthe art would understand that all reaction conditions, including, forexample, reaction solvent, reaction time, reaction temperature, reactionpressure, reactant ratio and whether or not the reaction should beperformed under an anhydrous or inert atmosphere, can be varied tooptimize the yield of the desired product and it is within their skillto do so.

The terms “about”, “substantially” and “approximately” as used hereinmean a reasonable amount of deviation of the modified term such that theend result is not significantly changed. These terms of degree should beconstrued as including a deviation of at least ±5% of the modified termif this deviation would not negate the meaning of the word.

The present description refers to a number of chemical terms andabbreviations used by those skilled in the art. Nevertheless,definitions of selected terms are provided for clarity and consistency.

The term “alkyl” as used herein, whether it is used alone or as part ofanother group, means straight or branched chain, saturated alkyl groups.The number of carbon atoms that are possible in the referenced alkylgroup are indicated by the prefix “C_(n1-n2)”. For example, the term °alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbonatoms. All alkyl groups are optionally fluoro-substituted.

The term “alkenyl” as used herein, whether it is used alone or as partof another group, means straight or branched chain, unsaturated alkylgroups containing at least one double bond. The number of carbon atomsthat are possible in the referenced alkyl group are indicated by theprefix “C_(n1-n2)”. For example, the term C₂₋₆alkenyl means an alkenylgroup having 2, 3, 4, 5 or 6 carbon atoms. All alkenyl groups areoptionally fluoro-substituted.

The term “alkynyl” as used herein, whether it is used alone or as partof another group, means straight or branched chain, unsaturated alkynylgroups containing at least one triple bond. The number of carbon atomsthat are possible in the referenced alkyl group are indicated by theprefix “C_(n1-n2)”. For example, the term C₂₋₆alkynyl means an alkynylgroup having 2, 3, 4, 5 or 6 carbon atoms. All alkynyl groups areoptionally fluoro-substituted.

The term “alkylene”, whether it is used alone or as part of anothergroup, means straight or branched chain, saturated alkylene group, thatis, a saturated carbon chain that contains substituents on two of itsends. The number of carbon atoms that are possible in the referencedalkylene group are indicated by the prefix “C_(n1-n2)”. For example, theterm C₂₋₆alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbonatoms. All alkylene groups are optionally fluoro-substituted.

The term “alkenylene” as used herein, whether it is used alone or aspart of another group, means a straight or branched chain, unsaturatedalkylene group, that is, an unsaturated carbon chain that containssubstituents on two of its ends and at least one double bond. The numberof carbon atoms that are possible in the referenced alkenylene group areindicated by the prefix “C_(n1-n2)”. For example, the termC₂₋₆alkenylene means an alkenylene group having 2, 3, 4, 5 or 6 carbonatoms. All alkenylene groups are optionally fluorosubstitutes.

The term “alkynylene” as used herein, whether it is used alone or aspart of another group, means a straight or branched chain, unsaturatedalkylene group, that is, an unsaturated carbon chain that containssubstituents on two of its ends and at least one triple bond. The numberof carbon atoms that are possible in the referenced alkynylene group areindicated by the prefix “C_(n1-n2)”. For example, the termC₂₋₆alkynylene means an alkynylene group having 2, 3, 4, 5 or 6 carbonatoms. All alkynylene groups are optionally fluorosubstituted.

The term “aryl” as used herein, whether it is used alone or as part ofanother group, refers to cyclic groups containing from 6 to 20 atoms andat least one carbocyclic aromatic ring. All aryl groups are optionallyfluorosubstituted.

The term “cycloalkyl,” as used herein, whether it is used alone or aspart of another group, refers to cyclic groups containing from 3 to 20atoms and at least one carbocyclic non aromatic ring. The number ofcarbon atoms that are possible in the referenced cycloalkyl group areindicated by the numerical prefix “C_(n1-n2)”. For example, the termC₃₋₁₀ cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms. All cycloalkyl groups are optionallyfluoro-substituted.

The term “heterocycloalkyl” as used herein, whether it is used alone oras part of another group, refers to cyclic groups containing at leastone non-aromatic ring containing from 3 to 20 atoms in which one or moreof the atoms are a heteroatom selected from O, S and N and the remainingatoms are C. Heterocycloalkyl groups are either saturated or unsaturated(i.e. contain one or more double bonds). When a heterocycloalkyl groupcontains the prefix C_(n1-n2) this prefix indicates the number of carbonatoms in the corresponding carbocyclic group, in which one or more,suitably 1 to 5, of the ring atoms is replaced with a heteroatom asselected from O, S and N and the remaining atoms are C. Allheterocycloalkyl groups are optionally fluoro-substituted. Theheteroatom in heterocycloalkyl groups is optionally substituted oroxidized where valency allows.

The term “heteroaryl” as used herein, whether it is used alone or aspart of another group, refers to cyclic groups containing at least oneheteroaromatic ring containing 5-20 atoms in which one or more of theatoms are a heteroatom selected from O, S and N and the remaining atomsare C. When a heteroaryl group contains the prefix C_(n1-n2) this prefixindicates the number of carbon atoms in the corresponding carbocyclicgroup, in which one or more, suitably 1 to 5, of the ring atoms isreplaced with a heteroatom as defined above. All heteroaryl groups areoptionally fluoro-substituted. The heteroatom in heteroaryl groups isoptionally substituted or oxidized where valency allows.

All cyclic groups, including aryl, heteroaryl, heterocycloalkyl andcycloalkyl groups, contain one or more than one ring (i.e. arepolycyclic). When a cyclic group contains more than one ring, the ringsmay be fused, bridged, spirofused or linked by a bond. All cyclic groupsare optionally fluoro-substituted.

The term “ring system” as used herein refers to a carbon- orheteroatom-containing ring system, that includes monocycles, fusedbicyclic and polycyclic rings, and bridged rings.

The term “polycyclic” as used herein means cyclic groups that containmore than one ring linked together and includes, for example, groupsthat contain two (bicyclic), three (tricyclic) or four (quadracyclic)rings. The rings may be linked through a single bond, a single atom(spirocyclic) or through two atoms (fused and bridged). All polycyclicgroups are optionally fluoro-substituted.

The term “benzofused” as used herein refers to a polycyclic group inwhich a benzene ring is fused with another ring.

A first ring being “fused” with a second ring means the first ring andthe second ring share two adjacent atoms there between.

A first ring being “bridged” with a second ring means the first ring andthe second ring share two non-adjacent atoms there between.

A first ring being “spirofused” with a second ring means the first ringand the second ring share one atom there between.

The term “fluoro-substituted” refers to the substitution of one or more,including all, available hydrogens in a referenced group with fluoro.

The terms “halo” or “halogen” as used herein, whether it is used aloneor as part of another group, refers to a halogen atom and includesfluoro, chloro, bromo and iodo.

The term “available”, as in “available hydrogen atoms” or “availableatoms” refers to atoms that would be known to a person skilled in theart to be capable of replacement by a substituent.

The term “protecting group” or “PG” and the like as used herein refersto a chemical moiety which protects or masks a reactive portion of amolecule to prevent side reactions in those reactive portions of themolecule, while manipulating or reacting a different portion of themolecule. After the manipulation or reaction is complete, the protectinggroup is removed under conditions that do not degrade or decompose theremaining portions of the molecule. The selection of a suitableprotecting group can be made by a person skilled in the art. Manyconventional protecting groups are known in the art, for example asdescribed in “Protective Groups in Organic Chemistry” McOmie, J. F. W.Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M.,“Protective Groups in Organic Synthesis”, John Wiley & Sons, 3^(1d)Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003,Georg Thieme Verlag (The Americas).

The term “deuterated” as used herein means that one or more, includingall, of the hydrogens on a group are replaced with deuterium (I.e. [²H].

The term “allylic alcohol” as used herein refers to a compoundcomprising a hydroxy substituent (—OH) attached to a spa hybridizedcarbon which is adjacent to a double bond.

The term “hydroxy aryl compound(s)” or “phenolics” as used herein refersto a compound comprising at least one hydroxy substituent on an arylring. In the case of phenolics, the aryl group is phenyl.

The term “ortho-allylated hydroxy aryl compound(s)” or “ortho-allylatedhydroxy phenolics” as used herein refers to a compound comprising anallylic group in a position ortho to a hydroxy group on an aryl ring. Inthe case of ortho-allylated hydroxy phenolics, the aryl group is phenyl.

The term “allylic group” as used herein refer to a substituentcomprising a double bond adjacent to a methylene which is covalentlyattached to the rest of the molecule.

The term “alumina” as used herein refers to aluminium oxide having thechemical formula: Al₂O₃ (H₂O)n where n is in the range of 0 to 1.

The term “acidic alumina” as used herein refers to activated aluminathat has been treated so that a 5% aqueous suspension of the alumina hasa pH less than 7.

The term “basic alumina” as used herein refers to activated alumina thathas been treated so that a 5% aqueous suspension of the alumina has a pHof greater than 7.

The term “neutral alumina” as used herein refers to activated aluminawherein a 5% aqueous suspension of the alumina has a neutral pH.

The term “activated alumina” as used herein refers to alumina that hasbeen treated under dehydroxylation conditions to provide a highly porousmaterial with a low water content.

The term “aluminum alkoxide” as used herein refers to a compound havinghaving one to three reactive alkoxy (—O-alkyl) groups per atom ofaluminum.

The term “aluminum isopropoxide” as used herein refers to a compoundhaving one to three reactive isopropoxy groups per atom of aluminum.

The term “non-protic solvent” as used herein includes both non polarsolvent and polar aprotic solvents.

The term “non-polar solvent” as used herein refers to a solvent that haslittle or no polarity and includes hydrophobic solvents.

The term “polar aprotic solvent” as used herein refers to a solvent asolvent that does not have an acidic proton and is polar.

The term “together with the phenyl ring to which said groups are bonded”as used herein means that the specified number of atoms in thepolycyclic ring system includes the 6 carbon atoms in the phenyl ring.

The term “unsubstituted”, as used herein means that the referenced atomdoes not contain a substituent group other than a hydrogen atom.

The term “substituted” as used herein means that the referenced atomcontains at least one substituent group other that a hydrogen atom.

The term “substituent group” as used herein refers to any chemicalgrouping, including groups comprising carbon atoms and/or heteroatoms)that is compatible with the reaction conditions of the processes of theapplication.

The term “major isomer” as used herein refers to a stereochemicalisomer, including a regional isomer, that is the most abundant isomer ina mixture of isomers of the same compound. Conversely, the term “minorisomer” as used herein refers to a stereochemical isomer, including aregional isomer, that is not the most abundant isomer in a mixture ofisomers of the same compound.

In the processes of the application, it is typical for the compounds,including starting materials and products to be present as a mixture ofisomers. For example, when it is shown that the R- or S-isomer is aproduct or starting material of a reaction, this means that that isomeris present in greater than 80%, 85%, 90%, 95%, 98% or 99% by weightbased on the total amount of R- and S-isomers.

The products of the processes of the application may be isolatedaccording to known methods, for example, the compounds may be isolatedby evaporation of the solvent, by filtration, centrifugation,chromatography or other suitable method.

II. Processes of the Application

The Applicants have developed an efficient one step process of preparingortho-allylated hydroxy aryl compounds (e.g. ortho-allylated phenolics).More specifically, the Applicants have discovered a general new approachto the ortho-allylation of unprotected hydroxy aryl compounds (e.gphenolics) using allylic alcohols through alumina promoted allylation innon-protic, for example hydrophobic, solvents. Using various allylicalcohols and phenolics, the Applicants have shown that when using thisprocess, the allylation occurs regiospecifically with the allylationoccurring preferentially at a position ortho to the hydroxy of thehydroxy aryl compound. Further, the process generally occurs with littleor no formation of the para-substituted and/or disubstituted product.

The Applicants have also discovered that the ortho-allylation ofunprotected hydroxy aryl compounds with allylic alcohols can be effectedusing alumina in combination with further additives includingdehydrating agents such as magnesium sulfate and various acids.Similarly, the ortho-allylation reaction with, for example, alumina anda dehydrating agents such as magnesium sulfate, was found to occurregiospecifically with the allylation occurring preferentially at aposition ortho to the hydroxy of the hydroxy aryl compound.

The Applicants have further surprisingly discovered that theortho-allylation of unprotected hydroxy aryl compounds with allylicalcohols can also be effected using aluminum alkoxides such as aluminumisopropoxide. Similarly, the ortho-allylation reaction with aluminumalkoxide such as aluminum isopropoxide was found to occurregiospecifically with the allylation occurring preferentially at aposition ortho to the hydroxy of the hydroxy aryl compound.

Accordingly, the application includes a process for preparing anortho-allylated hydroxy aryl compound comprising reacting an allylicalcohol with a hydroxy aryl compound in the presence of an aluminumcompound selected from alumina and aluminum alkoxides and in anon-protic solvent to form the ortho-allylated hydroxy aryl compound,wherein at least one carbon atom ortho to the hydroxy group in thehydroxy aryl compound is unsubstituted.

In an embodiment, the aluminum compound is alumina.

Accordingly, the application also includes a process for preparing anortho-allylated hydroxy aryl compound comprising reacting an allylicalcohol with a hydroxy aryl compound in the presence of alumina and in anon-protic solvent to form the ortho-allylated hydroxy aryl compound,wherein at least one carbon atom ortho to the hydroxy group in thehydroxy aryl compound is unsubstituted.

In an embodiment, the process provides the ortho isomer as the majorisomer. Accordingly, in an embodiment, the present application alsoincludes a process for selectively preparing an ortho-allylated hydroxyaryl compound comprising reacting an allylic alcohol with a hydroxy arylcompound in the presence of alumina and in a hydrophobic solvent to formthe ortho-allylated hydroxy aryl compound, wherein at least one carbonatom ortho to the hydroxy group in the hydroxy aryl compound isunsubstituted.

In an embodiment, the alumina is neutral, basic or acidic alumina. In anembodiment, the alumina is neutral alumina. In an embodiment, thealumina is basic alumina. In an embodiment, the alumina is acidicalumina.

In an embodiment, the non-protic solvent is a mixture of one or morenon-protic solvents. In an embodiment, the non-protic solvent, suitablynon-protic organic solvent, is a non-polar solvent or a polar aproticsolvent. In an embodiment, the non-polar solvent comprises hydrophobicsolvents. In an embodiment, the non-protic solvent is selected fromhexane, hexanes, heptane, heptanes, cyclohexane, petroleum ether,octane, diglyme, toluene, xylenes, benzene, chloroform, fluorinatedalkanes, dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate,carbon tetrachloride, tetrahydrofuran (THF), diethyl ether, diisopropylether, isooctane, methyl ethyl ketone, acetone, dimethyl sulfoxide,dimethylformamide, methyl tert-butyl ether, trichloroethane, n-butylacetate, chlorobenzene acetonitrile, and trifluorotoluene, and mixturesthereof. In an embodiment, the non-protic solvent is selected fromhexane, hexanes, heptane, heptanes, cyclohexane, petroleum ether,octane, diglyme, toluene, xylenes, benzene, chloroform, fluorinatedalkanes, dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate,carbon tetrachloride, tetrahydrofuran (THF), diethyl ether, diisopropylether, isooctane, methyl ethyl ketone, methyl tert-butyl ether,trichloroethane, n-butyl acetate, chlorobenzene acetonitrile, andtrifluorotoluene, and mixtures thereof. In an embodiment, the non-proticsolvent is a hydrophobic solvent selected from hexane, hexanes, heptane,heptanes, cyclohexane, toluene, xylene, dichloromethane and1,2-dichloroethane. In an embodiment, the hydrophobic solvent isselected from hexane, hexanes, toluene, dichloromethane and1,2-dichloroethane. In an embodiment, the hydrophobic solvent ishexanes. In an embodiment, the hydrophobic solvent is1,2-dichloroethane.

In an embodiment, the allylic alcohol is any compound that comprises ahydroxy group attached to an sp³ hybridized carbon that is adjacent todouble bond.

In an embodiment, the allylic alcohol is a naturally occurring allylicalcohol. In an embodiment, the allylic alcohol is a terpene alcohol, avitamin, or a cinnamyl alcohol.

In an embodiment, the allylic alcohol is a terpene alcohol. In anembodiment, the terpene alcohol is a monoterpene alcohol, diterpenealcohol or sequiterpene alcohol.

In an embodiment, the terpene alcohol comprises a prenyl (e.g.,3,3-dimethylallyl) functional,

or repeating prenyl functional groups. Therefore, in an embodiment, theterpene alcohol is prenol, geraniol, phytol, farnesol, or nerol.

In an embodiment, the monoterpene alcohol is isopiperitenol.

In an embodiment, the vitamin or derivative thereof is retinol.

In an embodiment, the allylic alcohol is cinnamyl alcohol. In anembodiment, the allylic alcohol is a substituted cinnamyl alcohol. In anembodiment, the substituted cinnamyl alcohol is substituted on the arylring.

In an embodiment, the hydroxy aryl compound or phenolic is phenol or asubstituted phenol. In an embodiment, the hydroxy aryl compound isresorcinol or a substituted resorcinol. In an embodiment, the hydroxylaryl compound is a phloroglucinol or a substituted phloroglucinol. In anembodiment, the hydroxy aryl compound is a hydroxy chalconoid or ameta-dihydroxychalconoid. In an embodiment, the hydroxyl aryl compoundis a moracin or a substituted moracin. In an embodiment, the hydroxylaryl compound is a stilbenoid. In an embodiment, the stilbenoid isresveratrol. In an embodiment, the hydroxy aryl compound is a polycyclichydroxy aryl compound (e.g. polyhydroxyphenolic compound).

In an embodiment, the hydroxy aryl compound is a hydroxy substitutedmonocyclic heteroaryl.

In an embodiment, the hydroxy aryl compound is a polycyclic hydroxy arylcompound. In an embodiment, the polycyclic hydroxy aryl compound is ahydroxy polyaromatic compound, steroid alcohol, a hydroxy benzofusedcompound, hydroxy polycyclic heterocycle or a hydroxy polycyclicheteroaryl.

In an embodiment, the polycyclic hydroxy aryl compound is a hydroxypolyaromatic compound. In an embodiment, the polyaromatic compound inthe hydroxy polyaromatic compound is a naphthalene, anthracene,phenanthrene, tetracene, chrysene, triphenylene, pyrene, pentacene,benzo[a]pyrene, corannulene, benzo[ghi]perylene, coronene, ovalene orbenzo[c]fluorine. In an embodiment, the polyaromatic compound in thehydroxy polyaromatic compound is a naphthalene. In an embodiment, thepolycyclic hydroxy aryl compound is a polyhydroxy polyaromatic compound.

In an embodiment, the polycyclic hydroxy aryl compound is a steroidalcohol. In an embodiment, the steroid alcohol is an estrogen. In anembodiment, the estrogen is estrone, estradiol, estriol, or estetrol. Inan embodiment, the steroid alcohol is an estrogen derivative. In anembodiment, the estrogen derivative is ethinyl estradiol.

In an embodiment, the polycyclic hydroxy aryl compound is a hydroxybenzofused compound. In an embodiment, the hydroxy benzofused compoundis a hydroxy chromone, or a meta-dihydroxy chromone. In an embodiment,the benzofused compound is a flavonol, isoflavonol, flavavonol orisoflavavonol. In an embodiment, the benzofused compound is a hydroxycoumarin. In an embodiment, the benzofused compound is a hydroxyxanthone. In an embodiment, the benzofused compound is abenzofurochromenone.

In an embodiment, the polycyclic hydroxy aryl compound is a hydroxysubstituted polycyclic heterocycle or heteroaryl. In an embodiment,hydroxy substituted polycyclic heteroaryl is hydroxy substitutedindolyl, isoindolyl or benzofuranyl.

In an embodiment, the ortho-allylated hydroxy aryl compound is anaturally occurring compound. In an embodiment, the ortho-allylatedhydroxy aryl compound is an ortho-allylated resorcinol, anortho-allylated phloroglucinol, an ortho-allylated chalcone, andortho-allylated cannabinoid, an ortho-allylated meta-dihydroxy chalcone,an ortho-allylated hydroxy chalconoid, an ortho-allylatedmeta-dihydroxychalconoid, an ortho-allylated moracin, an ortho-allylatedstilbenoid, an ortho-allylated hydroxy naphthalene, an ortho-allylatedhydroxy anthracene, an ortho-allylated hydroxy phenanthrene, anortho-allylated hydroxy tetracene, an ortho-allylated hydroxy chrysene,an ortho-allylated hydroxy triphenylene, an ortho-allylated hydroxypyrene, an ortho-allylated hydroxy pentacene, an ortho-allylated hydroxybenzo[a]pyrene, an ortho-allylated hydroxy corannulene, anortho-allylated hydroxy benzo[ghi]perylene, an ortho-allylated hydroxycoronene, an ortho-allylated hydroxy ovalene, an ortho-allylated hydroxybenzo[c]fluorine, an ortho-allylated steroid alcohol, an ortho-allylatedflavanonol, an ortho-allylated isoflavanonol, an ortho-allylatedflavonols, an ortho-allylated isoflavonol, an ortho-allylated steroid,an ortho-allylated hydroxy chromone, ortho-allylated meta-dihydroxychromone, an ortho-allylated hydroxy xanthone or an ortho-allylatedcoumarin.

In an embodiment, the ortho-allylated hydroxy aryl compound comprises aprenyl (e.g. 3,3-dimethylallyl) functional group or repeating prenylfunctional groups such as prenyl, geranyl, phytyl, farnesyl, or neryl.Therefore, in an embodiment, the ortho-allylated hydroxy aryl compoundis an ortho-prenylated hydroxy aryl compound or an ortho-prenylatedphenolic.

In an embodiment, the ortho-allylated cannabinoid is selected fromcannabidiol, cannabidivarin, cannabigerol, cannabigerorcin andcannabigerivarin. In an embodiment, the ortho-allylated cannabinoid isselected from cannabidivarin, cannabigerol, cannabigerorcin andcannabigerivarin. In an embodiment, the ortho-allylated cannabinoid iscannabidiol.

In an embodiment, the ortho-allylated hydroxy aryl compound is selectedfrom an ortho-allylated flavanonol, an ortho-allylated flavonol, anortho-allylated isoflavanonol, an ortho-allylated isoflavonol,isoflavonol or an ortho-allylated hydroxy chromone.

In an embodiment, the ortho-allylated hydroxy aryl compound is anortho-allylated coumarin.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound comprises mixing the allylic alcohol, hydroxy aryl compound andthe aluminum compound in the non-protic solvent under continuous flowreaction conditions using for example continuous processors. Continuousflow processors comprise a combination of mixing and conveying meansthat allow the reactants to flow into or through a mixing means, reactto form products and allow the products to flow out of the mixing meansfor isolation and purification on a continuous basis. In the mixing andconveying means, the reaction conditions (such as temperature andpressure) can be controlled. Such continuous flow processors are wellknown in the art. In an embodiment, the flow reaction conditionscomprise a heterogeneous reactor comprising for example a fixed bedreactor, a trickle bed reactor, a moving bed reactor or a rotation bedreactor. In some embodiments, the aluminum compound is comprised in thebed reactor and the other reagents, including the compounds of FormulaII and III and optional additives flow through the bed to be convertedinto compound of Formula I.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound comprises mixing the allylic alcohol, hydroxy aryl compound andthe aluminum compound in the non-protic solvent under batch reactionconditions.

In an embodiment, when forming a mono ortho-allylated hydroxy arylcompound, the forming of the ortho-allylated hydroxy aryl compoundfurther comprises mixing the allylic alcohol, the hydroxy aryl compoundand the aluminum compound in the non-protic solvent with the addition ofexcess amounts of the hydroxy aryl compound. In an embodiment, theforming of the ortho-allylated hydroxy aryl compound comprises mixingthe allylic alcohol, hydroxy aryl compound and aluminum compound in thenon-protic solvent with the addition of, for example, about 1.1 to about5, about 1.1 to about 4, about 1.1 to about 3, about 2 to about 5, about2 to about 4, about 3 to about 4, or about 1.5 to about 3 molarequivalents of the hydroxy aryl compound relative to the amount of theallylic alcohol. In an embodiment, the forming of the ortho-allylatedhydroxy aryl compound comprises mixing the allylic alcohol, hydroxy arylcompound and aluminum compound in the non-protic solvent with theaddition of, for example, about 1 to about 5, about 1 to about 4, about1 to about 3, or about 1.5 to about 3 molar equivalents of the hydroxyaryl compound relative to the amount of the allylic alcohol. In anembodiment, the conditions forming of the ortho-allylated hydroxy arylcompound comprises mixing the allylic alcohol, hydroxy aryl compound andaluminum compound in the non-protic solvent with about 1.5 molarequivalents of the hydroxy aryl compound relative to the amount of theallylic alcohol.

In an embodiment, when forming an mono ortho-allylated hydroxy arylcompound the forming of the ortho-allylated hydroxy aryl compoundfurther comprises mixing the allylic alcohol, the hydroxy aryl compoundand the aluminum compound in the non-protic solvent with about 1.5 toabout 4 molar equivalents, about 1.5 to about 5 molar, about 2 to about5, about 2 to about 4, or about 3 to about 4 molar equivalents of thecompound of Formula (II) relative to the amount of the compound ofFormula (III). In an embodiment, the forming of the ortho-allylatedhydroxy aryl compound further comprises mixing the allylic alcohol, thehydroxy aryl compound and the aluminum compound in the non-proticsolvent with about 3 to about 4 molar equivalents of the compound ofFormula (II) relative to the amount of the compound of Formula (III).

In an embodiment, when it is desired to add additional allyl groups,beyond the ortho-allyl group (i.e. a polyallylated hydroxy aryl compoundsuch as a di-, tri- and tetra-allylated hydroxy aryl compound), theforming of the polyallylated hydroxy aryl compound further comprisesmixing the allylic alcohol, the hydroxy aryl compound and the aluminumcompound in the non-protic solvent with the addition of excess amountsof the allylic alcohol. In an embodiment, the forming of thepolyallylated hydroxy aryl compound comprises mixing the allylicalcohol, hydroxy aryl compound and aluminum compound in the non-proticsolvent with the addition of, for example, about 1.1 to about 5, about1.1 to about 4, about 1.1 to about 3, about 2 to about 5, 1.5 to about4, about 2 to about 4, about 3 to about 4, about 3 to about 5, about 4to about 5, or about 1.5 to about 3 molar equivalents of the allylicalcohol relative to the amount of the hydroxy aryl compound. In anembodiment, the conditions forming of the polyallylated hydroxy arylcompound comprises mixing the allylic alcohol, hydroxy aryl compound andaluminum compound in the non-protic solvent with about 3 to about 4,about 3 to about 5, or about 4 to about 5 molar equivalents of theallylic alcohol relative to the amount of the hydroxy aryl compound.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound further comprises mixing the allylic alcohol, the hydroxy arylcompound and the aluminum compound in the non-protic solvent with theaddition of the aluminum compound in the amount of about 1 g to about 3g, about 1.5 g to about 3 g, or about 1.5 g to about 2 g per 1 mmol ofthe allylic alcohol. In an embodiment, the forming of theortho-allylated hydroxy aryl compound comprises mixing the allylicalcohol, the hydroxy aryl compound and the aluminum compound in thenon-protic solvent with the addition of the aluminum compound in theamount of about 2 g per 1 mmol of the allylic alcohol. In an embodiment,the aluminum compound is alumina. In an embodiment, the alumina isacidic alumina. In an embodiment, the acidic alumina, has a pH of lessthan about 6.5, about 6, about 5.5, about 5.0, about 4.5 or about 4.0.In an embodiment, the acidic alumina has a pH of less than about 5.5,about 5.0, about 4.5 or about 4.0. In an embodiment, the acidic alumina,has a pH of about 4.5.

In an embodiment, the alumina is basic alumina. In an embodiment, thebasic alumina, has a pH of greater than about 7.5, about 8, about 8.5,about 9.0, about 9.5, about 10 or about 10.5. In an embodiment, thebasic alumina has a pH of greater than about 9.0, about 9.5, about 10 orabout 10.5. In an embodiment, the basic alumina has a pH of about 10.

In an embodiment, the alumina is neutral alumina. In an embodiment, theneutral alumina has a pH of about 7.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound further comprises mixing the allylic alcohol, the hydroxy arylcompound and the aluminum compound in the non-protic solvent to form areaction mixture and heating the reaction mixture.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound further comprises mixing the allylic alcohol, the hydroxy arylcompound and the aluminum compound in the non-protic solvent to form areaction mixture and heating the reaction mixture to the boiling point(refluxing temperature) of the solvent. In an embodiment, the forming ofthe ortho-allylated hydroxy aryl compound further comprises mixing theallylic alcohol, the hydroxy aryl compound and the alumina in DCE toform a reaction mixture and heating the reaction mixture to about 40° C.to about 83° C., about 60° C. to about 83° C., about 70° C. to about 83°C., or about 83° C.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound further comprises mixing the allylic alcohol, the hydroxy arylcompound and the aluminum compound in the non-protic solvent to form areaction mixture, and heating the reaction mixture for about 4 hours toabout 24 hours, about 6 hours to about 24 hours, or about 12 hours to 24hours. In an embodiment, the forming of the ortho-allylated hydroxy arylcompound further comprises mixing the allylic alcohol, the hydroxy arylcompound and the aluminum compound in the non-protic solvent to form areaction mixture, and heating the reaction mixture at the refluxingtemperature of the solvent for about 24 hours.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound comprises mixing the allylic alcohol, the hydroxy aryl compoundand the aluminum compound in the non-protic solvent to form a reactionmixture and heating the reaction mixture under microwave synthesisconditions. Therefore, in an embodiment, the forming of theortho-allylated hydroxy aryl compound comprises mixing the allylicalcohol, the hydroxy aryl compound and the aluminum compound in thenon-protic solvent to form a reaction mixture and heating the reactionmixture using microwave radiation. In an embodiment, the microwavesynthesis conditions comprise heating the reaction mixture in amicrowave reactor. In an embodiment, the microwave synthesis conditionscomprise heating the reaction mixture in a microwave reactor to about100° C. to about 175° C., about 125° C. to about 175° C., or about 150°C.

In an embodiment, after heating, the reaction mixture is cooled andfiltered through a filter agent, such as Celite® or silica, and thefiltrate is concentrated for example, by evaporation such asrotoevaporation, to provide a crude product that comprises theortho-allylated hydroxy aryl compound. In an embodiment, the crudeproduct is then purified using chromatography such as columnchromatography using a suitable solvent or mixture of solvents, or anyother known purification method.

In an embodiment, the column chromatography is flash columnchromatography. In an embodiment, the suitable mixture of solvents forcolumn chromatography is ethyl acetate and hexane.

In an embodiment, the crude product is purified by crystallization. Inan embodiment, the crude product is purified by crystallization withoutthe use of chromatography. In an embodiment, the crude product iscrystallized using hexane, hexanes, heptane, heptanes, cyclohexane,toluene, xylene and the like. In an embodiment, the crude product is acrude ortho-allylated cannabinoid and the crude product is crystallizedusing hexane, hexanes, heptane, heptanes, or cyclohexane. In anembodiment, the crude product is a crude ortho-allylated cannabinoid andthe crude product is crystallized with heptane.

In an embodiment, the crude product is purified by distillation. In anembodiment, the crude product is purified by distillation without theuse of chromatography. In an embodiment, the crude product is a crudeortho-allylated cannabinoid and the crude product is purified bydistillation.

In an embodiment, the process of the application can be performedconsecutively such that the ortho-allylated hydroxy aryl compound formedfrom a first process of the application is used as the hydroxy arylcompound in a subsequent process of the application. Accordingly, in theembodiment, the hydroxy aryl compound is the ortho-allylated hydroxyaryl formed by a process of the application described above.

In an embodiment, the process provides the ortho-allylated hydroxy arylcompound as the major product of the process. In an embodiment, theprocess provides the ortho-allylated hydroxy aryl compound in a yield ofgreater than about 15%, about 20%, about 25%, about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90% or about 95%.

In an embodiment, the process provides the ortho-allylated hydroxy arylcompound in a yield of greater an about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90% or about 95%. In anembodiment, the process provides the ortho-allylated hydroxy arylcompound in a yield of greater an about 70%, about 75%, about 80%, about85%, about 90% or about 95%.

The Applicants have also shown that an ortho-allylated hydroxy arylcompound can be formed by reacting an allylic alcohol with a hydroxyaryl compound in the presence of alumina and further additives includingdehydrating reagents such as magnesium sulfate and/or various acids.Therefore, the process of the application further comprises the use of adehydrating reagent and/or an acid in combination with the aluminumcompound. Therefore, the application also includes a process forpreparing an ortho-allylated hydroxy aryl compound comprising reactingan allylic alcohol with a hydroxy aryl compound in the presence ofalumina and a dehydrating agent in a non-protic solvent to form theortho-allylated hydroxy aryl compound, wherein at least one carbon atomortho to the hydroxy group in the hydroxy aryl compound isunsubstituted.

In an embodiment, the dehydrating agent is selected from magnesiumsulfate, sodium sulfate, aluminum phosphate, calcium oxide, cyanuricchloride, orthoformic acid, phosphorus pentoxide, sulfuric acid andmolecular sieves, and combinations thereof. In an embodiment, thedehydrating agent is selected from magnesium sulfate, sodium sulfate,aluminum phosphate, calcium oxide, cyanuric chloride, orthoformic acid,phosphorus pentoxide, and molecular sieves, and combinations thereof. Inan embodiment, the dehydrating agent is magnesium sulfate.

The Applicants have found that the alumina can be acidic alumina. Itwould be appreciated by a person skilled in the art that acid can beadded to the alumina in process of the application. Therefore, in anembodiment, the application also includes a process for preparing anortho-allylated hydroxy aryl compound comprising reacting an allylicalcohol with a hydroxy aryl compound in the presence of alumina and anacid in a non-protic solvent to form the ortho-allylated hydroxy arylcompound, wherein at least one carbon atom ortho to the hydroxy group inthe hydroxy aryl compound is unsubstituted.

In an embodiment the acid is selected from a Lewis acid and a Bronstedacid, and a combination thereof. In an embodiment, the Lewis acid isselected from boron trichloride, boron trifluoride, boron trifluoridediethyl etherate, iron (III) bromide, iron (III) chloride, aluminumchloride, aluminum bromide, tin (IV) chloride, titanium (IV) chloride,and titanium (IV) isopropoxide and a combination thereof. In anembodiment, the Bronsted acid is selected from hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid, acetic acid,trifluoroacetic acid, toluene sulfonic acid, trichloroacetic acid, boricacid, oleic acid, palmitic acid, and camphor sulfonic acid and acombination thereof.

In an embodiment, the allylic alcohol, hydroxy aryl compound andortho-allylated hydroxy aryl compound are as described above.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound in the presence of alumina and a further additive such as adehydrating agent and/or an acid in a non-protic solvent are underconditions as described above for the forming of the ortho-allylatedhydroxy aryl compound in the presence of aluminum compound such asalumina alone in a non-protic solvent.

The Applicants have further shown that an ortho-allylated hydroxy arylcompound can be formed by reacting an allylic alcohol with a hydroxyaryl compound in the presence of an aluminum alkoxide such as aluminumisopropoxide. Therefore, in an embodiment, the aluminum compound isaluminum alkoxide.

Accordingly, the application also includes a process for preparing anortho-allylated hydroxy aryl compound comprising reacting an allylicalcohol with a hydroxy aryl compound in the presence of an aluminumalkoxide and in a non-protic solvent to form the ortho-allylated hydroxyaryl compound, wherein at least one carbon atom ortho to the hydroxygroup in the hydroxy aryl compound is unsubstituted.

In an embodiment, the aluminum alkoxide dissolves in the non-proticsolvent. Therefore, the reacting an allylic alcohol with a hydroxy arylcompound in the presence of an aluminum alkoxide and in a non-proticsolvent to form the ortho-allylated hydroxy aryl compound, wherein atleast one carbon atom ortho to the hydroxy group in the hydroxy arylcompound is unsubstituted is a homogenous reaction.

In an embodiment, the allylic alcohol, hydroxy aryl compound andortho-allylated hydroxy aryl compound are as described above.

In an embodiment, the forming of the ortho-allylated hydroxy arylcompound in the presence of aluminum alkoxide in a non-protic solventare under conditions as described above for the forming of theortho-allylated hydroxy aryl compound in the presence of alumina in anon-protic solvent.

In an embodiment, the aluminum alkoxide is an aluminum C₁₋₁₀alkoxide. Inan embodiment, the aluminum alkoxide is an aluminum C₁₋₆alkoxide. In anembodiment, the aluminum alkoxide is an aluminum C₁₋₆alkoxide. In anembodiment, the aluminum alkoxide is selected from aluminum methoxide,aluminum ethoxide, aluminum-n-propoxide, aluminum isopropoxide,aluminum-n-butoxide, aluminum-sec-butoxide, aluminum-iso-propoxide andaluminum tert-butoxide. In an embodiment, the aluminum alkoxide isaluminum isopropoxide. In an embodiment, the allylic alcohols and thehydroxy aryl compounds are both available from commercial sources or canbe prepared using methods known in the art.

In an embodiment, the alumina (e.g., neutral, basic and acidic alumina)is available from commercial sources.

In an embodiment, the aluminum alkoxide (e.g aluminum isopropoxide) isavailable from commercial sources.

In an embodiment, the application further includes a process forpreparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in the presence of an aluminum compound selected from alumina andaluminum alkoxides and in a non-protic solvent to form the compound ofFormula (I),

-   -   wherein:    -   each R¹ is independently OH, halo, CN, NO₂ or COOH, or        independently selected from any suitable unsubstituted or        substituted alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, Z-alkyl, Z-alkenyl,        Z-alkynyl, Z-cycloalkyl, Z-heterocycloalkyl, Z-aryl, Z and        Z-heteroaryl, wherein the substituents are selected from OH,        halo, alkyl, O-alkyl, aryl, cycloalkyl, heteroaryl and        heterocycloalkyl groups, the latter 4 groups being optionally        substituted with one or more substituents selected from OH,        alkyl, alkenyl, and O-alkyl; or when n is greater than 1, two R¹        groups are linked together to form an unsubstituted or        substituted polycyclic ring system having 8 or more atoms        together with the phenyl ring to which said R¹ groups are        bonded, and in which one or more carbon atoms in said polycyclic        ring system is optionally replaced with a heteromoiety selected        from NR⁶, O and S; wherein the polycyclic ring system is        optionally substituted with one or more substituents selected        from ═O, OH, halo, alkyl, alkenyl, alkynyl, O-alkyl, O-alkenyl,        O-alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl        the latter 10 groups being optionally substituted with one or        more substituents selected from OH, alkyl, alkenyl, and O-alkyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is H;    -   R³ is selected from H and any suitable unsubstituted or        substituted alkyl;    -   R⁴ is H, or selected from any suitable unsubstituted or        substituted alkyl; aryl, alkylenearyl, heteroaryl, and        alkyleneheteroaryl;    -   R⁵ is H, or selected from any suitable unsubstituted or        substituted alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, wherein the substituents        are selected from OH, halo, alkyl, O-alkyl, aryl, cycloalkyl,        heteroaryl and heterocycloalkyl groups; or    -   any two of R², R³, R⁴ and R⁵ are linked together to form an        unsubstituted or substituted monocyclic or polycyclic ring        system having 4 or more atoms together with the carbon atoms to        which said any two of R², R³, R⁴ and R⁵ are bonded, wherein the        monocyclic or polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo, alkyl,        alkenyl, alkynyl, O-alkyl, O-alkenyl, O-alkynyl, aryl,        heteroaryl, cycloalkyl, and heterocycloalkyl, the latter 10        groups being optionally substituted with OH, alkyl, alkenyl, and        O-alkyl;    -   R⁶ and R⁷ are independently selected from H and unsubstituted or        substituted alkyl;    -   n is an integer selected from 0 to 4, and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the aluminum compound is alumina.

Therefore, in an embodiment, the application further includes a processfor preparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in presence of alumina and in a hydrophobic solvent under conditions toform the compound of Formula (I),

-   -   wherein:    -   each R¹ is independently OH, halo, CN, NO₂ or COOH, or        independently selected from any suitable unsubstituted or        substituted alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, Z-alkyl, Z-alkenyl,        Z-alkynyl, Z-cycloalkyl, Z-heterocycloalkyl, Z-aryl, Z and        Z-heteroaryl, wherein the substituents are selected from OH,        halo, alkyl, O-alkyl, aryl, cycloalkyl, heteroaryl and        heterocycloalkyl groups, the latter 4 groups being optionally        substituted with one or more substituents selected from OH,        alkyl, alkenyl, alkynyl, O-alkyl, or O-alkenyl; or    -   when n is greater than 1, two R¹ groups are linked together to        form an unsubstituted or substituted polycyclic ring system        having 8 or more atoms together with the phenyl ring to which        said R¹ groups are bonded, and in which one or more carbon atoms        in said polycyclic ring system is optionally replaced with a        heteromoiety selected from NR⁶, O and S; wherein the polycyclic        ring system is optionally substituted with one or more        substituents selected from ═O, OH, halo, alkyl, alkenyl,        alkynyl, O-alkyl, O-alkenyl, O-alkynyl, aryl, heteroaryl,        cycloalkyl, and heterocycloalkyl the latter 10 groups being        optionally substituted with one or more substituents selected        from OH, alkyl, alkenyl, and O-alkyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is selected from H and any suitable unsubstituted or        substituted alkyl;    -   R³ is selected from H and any suitable unsubstituted or        substituted alkyl;    -   R⁴ is H, or selected from any suitable unsubstituted or        substituted alkyl; aryl, alkylenearyl, heteroaryl, and        alkyleneheteroaryl;    -   R⁵ is H, or selected from any suitable unsubstituted or        substituted alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, wherein the substituents        are selected from OH, halo, alkyl, O-alkyl, aryl, cycloalkyl,        heteroaryl and heterocycloalkyl groups; or    -   any two of R², R³, R⁴ and R⁵ are linked together to form an        unsubstituted or substituted monocyclic or polycyclic ring        system having 4 or more atoms together with the carbon atoms to        which said any two of R², R³, R⁴ and R⁵ are bonded, wherein the        monocyclic or polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo, alkyl,        alkenyl, alkynyl, O-alkyl, O-alkenyl, O-alkynyl, aryl,        heteroaryl, cycloalkyl, and heterocycloalkyl, the latter 10        groups being optionally substituted with OH, alkyl, alkenyl, and        O-alkyl;    -   R⁶ and R⁷ are independently selected from H and unsubstituted or        substituted alkyl;    -   n is an integer selected from 0 to 4, and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the application further includes a process forpreparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in the presence of an aluminum compound selected from alumina andaluminum alkoxides and in a non-protic solvent to form the compound ofFormula (I),

-   -   wherein:    -   each R¹ is independently selected from OH, halo, CN, NO₂, COOH,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈        cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        cycloalkyl, C₃₋₁₈heterocycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl,        C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈aryl,        C₂₋₁₆alkynyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyl, Z—C₂₋₁₆alkenyl,        Z—C₂₋₁₆alkynyl, Z—C₃₋₁₈cycloalkyl,        Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈        cycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl,        Z—C₃₋₁₈heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, Z—C₆₋₁₈aryl, Z—C₁₋₁₆alkyleneC₆₋₁₈aryl,        Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkynyleneC₆₋₁₈aryl,        Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,        Z—C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl, and        Z—C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,    -   wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl heterocycloalkyl, aryl, and heteroaryl        groups are optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; or    -   when n is greater than 1, two R¹ groups are linked together to        form a polycyclic ring system having 8 or more atoms together        with the phenyl ring to which said groups are bonded, and in        which one or more carbon atoms in said polycyclic ring system is        optionally replaced with a heteromoiety selected from NR⁶, O and        S, wherein the polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,        C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl,        C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heteroaryl, the latter 4 groups        being optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and        C₂₋₁₆alkenyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is H,    -   R³ is selected from H and C₁₋₆alkyl,    -   R⁴ is selected from H, C₁₋₆alkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₅₋₁₈ heteroaryl, and        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl;    -   R⁵ is selected from H, C₁₋₂₆alkyl, C₂₋₂₆alkenyl, C₂₋₂₆alkynyl,        C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈cycloalkyl,        C₃₋₁₈ heterocycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        C₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, C₆₋₁₈ aryl, C₁₋₁₆alkyleneC₆₋₁₈ aryl,        C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C₂₋₁₆alkynyleneC₆₋₁₈ aryl,        C₅₋₁₈heteroaryl, C₂₋₁₆alkyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,        wherein all cycloalkyl, heterocycloalkyl, aryl and heteroaryl        are optionally substituted with one or more substituents        selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,        C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl,        C₁₋₁₆alkyleneOR⁹ C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹,        SO₃C₁₋₁₆alkyl, SO₃C₆₋₁₆ aryl, and SO₃C₅₋₁₈ heteroaryl        substituted with C₁₋₁₆alkyl; or    -   any two of R², R³, R⁴ and R⁵ are linked together to form an        unsubstituted or substituted monocyclic or polycyclic ring        system having 4 or more atoms together with the carbon atoms to        which said any two of R², R³, R⁴ and R⁵ are bonded, wherein the        monocyclic or polycyclic ring system is optionally substituted        with one or more substituents selected ═O, OH, halo, C₁₋₁₆alkyl,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈cycloalkyl,        C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups        being optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and        C₂₋₁₆alkenyl;    -   R⁶, R⁷, R⁸ and R⁹ are independently selected from H and        C₁₋₆alkyl;    -   n is an integer selected from 0 to 4, and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the aluminum compound is alumina. Therefore, in anembodiment, the process of the application comprises reacting thecompound of Formula (II) as defined above with a compound of Formula(III) as defined above in the presence of alumina and in a non-proticsolvent to form the compound of Formula (I) as defined above.

Therefore, in an embodiment, the application further includes a processfor preparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in presence of alumina and in a hydrophobic solvent under conditions toform the compound of Formula (I),

-   -   wherein:    -   each R¹ is independently selected from OH, halo, CN, NO₂, COOH,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈        cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        cycloalkyl, C₃₋₁₈heterocycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl,        C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈aryl,        C₂₋₁₆alkynyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl, 16alkyl, Z—C₂₋₁₆alkenyl,        Z—C₂₋₁₆alkynyl, Z—C₃₋₁₈ cycloalkyl,        Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈        cycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl,        Z—C₃₋₁₈heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, Z—C₆₋₁₈aryl, Z—C₁₋₁₆alkyleneC₆₋₁₈aryl,        Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkynyleneC₆₋₁₈aryl,        Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,        Z—C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl, and        Z—C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,    -   wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl heterocycloalkyl, aryl, and heteroaryl        groups are optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; or    -   when n is greater than 1, two R¹ groups are linked together to        form a polycyclic ring system having 8 or more atoms together        with the phenyl ring to which said groups are bonded, and in        which one or more carbon atoms in said polycyclic ring system is        optionally replaced with a heteromoiety selected from NR⁶, O and        S, wherein the polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈        heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups being        optionally substituted with one or more substituents selected        from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is selected from H and C₁₋₆alkyl,    -   R³ is selected from H and C₁₋₆alkyl,    -   R⁴ is selected from H, C₁₋₆alkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₅₋₁₈ heteroaryl, and        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl;    -   R⁵ is selected from H, C₁₋₂₆alkyl, C₂₋₂₆alkenyl, C₂₋₂₆alkynyl,        C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈cycloalkyl,        C₃₋₁₈ heterocycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        C₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, C₆₋₁₈aryl, C₁₋₁₆alkyleneC₆₋₁₈ aryl,        C₂₋₁₆alkenyleneC₆₋₁₈aryl, C₂₋₁₆alkynyleneC₆₋₁₈aryl,        C₅₋₁₈heteroaryl, C₂₋₁₆alkyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,        wherein all cycloalkyl, heterocycloalkyl, aryl and heteroaryl        are optionally substituted with one or more substituents        selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,        C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁹        C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹, SO₃C₁₋₁₆alkyl,        SO₃C₆₋₁₆aryl, and SO₃C₅₋₁₈heteroaryl substituted with        C₁₋₁₆alkyl; or    -   any two of R², R³, R⁴ and R⁵ are linked together to form an        unsubstituted or substituted monocyclic or polycyclic ring        system having 4 or more atoms together with the carbon atoms to        which said any two of R², R³, R⁴ and R⁵ are bonded, wherein the        monocyclic or polycyclic ring system is optionally substituted        with one or more substituents selected ═O, OH, halo, C₁₋₁₆alkyl,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈        heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups being        optionally substituted with one or more substituents selected        from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl;    -   R⁶, R⁷, R⁸ and R⁹ are independently selected from H and        C₁₋₆alkyl;    -   n is an integer selected from 0 to 4, and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the process selectively forms the compound of Formula(I) as the major isomer. Accordingly, in an embodiment, the presentapplication also includes a process for selectively preparing a compoundof Formula (I) comprising reacting a compound of Formula (II) with acompound of Formula (III) in presence of an aluminum compound and in anon-protic solvent under forming of the compound of Formula (I), whereinthe compounds of Formulae (I) to (III) are as defined above.

In an embodiment, the aluminum compound is alumina. In an embodiment,the alumina is neutral, basic or acidic alumina. In an embodiment, thealumina is neutral alumina. In an embodiment, the alumina is basicalumina. In an embodiment, the alumina is acidic alumina.

In an embodiment, the non-protic solvent is a mixture of one or morenon-protic solvents. In an embodiment, the non-protic solvent, suitablynon-protic organic solvent, is a non-polar solvent or a polar aproticsolvent. In an embodiment, the non-polar solvent comprises hydrophobicsolvents. In an embodiment, the non-protic solvent is selected fromhexane, hexanes, heptane, heptanes, cyclohexane, petroleum ether,octane, diglyme, toluene, xylenes, benzene, chloroform, fluorinatedalkanes, dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate,carbon tetrachloride, tetrahydrofuran (THF), diethyl ether, diisopropylether, isooctane, methyl ethyl ketone, acetone, dimethyl sulfoxide,dimethylformamide methyl tert-butyl ether, trichloroethane, n-butylacetate, chlorobenzene acetonitrile, and trifluorotoluene, and mixturesthereof. In an embodiment, the non-protic solvent is selected fromhexane, hexanes, heptane, heptanes, cyclohexane, petroleum ether,octane, diglyme, toluene, xylenes, benzene, chloroform, fluorinatedalkanes, dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate,carbon tetrachloride, tetrahydrofuran (THF), diethyl ether, diisopropylether, isooctane, methyl ethyl ketone, methyl tert-butyl ether,trichloroethane, n-butyl acetate, chlorobenzene acetonitrile, andtrifluorotoluene, and mixtures thereof. In an embodiment, the non-proticsolvent is a hydrophobic solvent selected from hexane, hexanes, heptane,heptanes, cyclohexane, toluene, xylene, dichloromethane and1,2-dichloroethane. In an embodiment, the hydrophobic solvent isselected from hexane, hexanes, toluene, dichloromethane and1,2-dichloroethane. In an embodiment, the hydrophobic solvent ishexanes. In an embodiment, the hydrophobic solvent is1,2-dichloroethane.

In an embodiment, Z is selected from O, C(O), and CO₂. In an embodiment,Z is selected from O and C(O). In an embodiment, Z is O. In anembodiment, Z is C(O).

In an embodiment, each R¹ is independently selected from OH, halo, CN,NO₂, COOH, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈ cycloalkyl,C₁₋₁₂alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, C₁₋₁₂alkyleneC₃₋₁₈heterocycloalkyl,C₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl, C₆₋₁₈aryl,C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈aryl, C₅₋₁₈heteroaryl,C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,Z—C₁₋₁₆alkyl, Z—C₂₋₁₆alkenyl, Z—C₂₋₁₆alkynyl, Z—C₅₋₁₈ cycloalkyl,Z—C₁₋₁₂alkyleneC₃₋₁₈ cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,Z—C₅₋₁₈ heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,Z—C₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl, Z—C₆₋₁₈ aryl,Z—C₁₋₁₂alkyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₂alkyleneC₅₋₁₈heteroaryl, andZ—C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, wherein all alkyl, alkenyl, alkynyl,alkylene, alkenylene alkynylene cycloalkyl heterocycloalkyl, aryl andheteroaryl groups are optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl.

In an embodiment, each R¹ is independently selected from OH, halo, CN,NO₂, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈ cycloalkyl, C₁₋₁₂alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,C₁₋₁₂alkyleneC₃₋₁₈ heterocycloalkyl, C₁₋₁₂alkenyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl, C₁₋₁₂alkyleneC₆₋₁₈aryl,C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,Z—O₁₋₁₂alkyl, Z—C₂₋₁₆alkenyl, Z—C₅₋₁₈ cycloalkyl, Z—C₁₋₁₂alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl, Z—C₅₋₁₈ heterocycloalkyl,Z—C₁₋₁₂alkyleneC₃₋₁₈ heterocycloalkyl,Z—C₁₋₁₂alkenyleneC₃₋₁₈heterocycloalkyl, Z—O₆₋₁₈aryl,Z—C₁₋₁₂alkyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₅₋₁₈heteroaryl,Z—C₁₋₁₂alkyleneC₅₋₁₈heteroaryl, and Z—C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylenecycloalkyl heterocycloalkyl, aryl and heteroaryl groups are optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, andOC₂₋₁₆alkynyl.

In an embodiment, each R¹ is independently selected from OH, Br, Cl, F,NO₂, CN, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl and Z—C₁₋₁₂alkyl wherein each alkyl,alkenyl and alkynyl, groups are optionally substituted with one or moresubstituents selected from OH, F, and OC₁₋₁₂alkyl.

In an embodiment, Z is O and each R¹ is independently selected from OH,Br, Cl, F, NO₂, CN, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl andO—C₁₋₁₂alkyl wherein each alkyl, alkenyl, and alkynyl groups areoptionally substituted with one or more substituents selected from OH,F, and OC₁₋₁₂alkyl.

In an embodiment, each R¹ is independently selected from OH, Br, Cl, F,NO₂, CN, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, O—C₁₋₁₂alkyl and C₁₋₁₆alkyleneOH.In an embodiment, each R¹ is independently selected from OH, Br, Cl, F,NO₂, CN, C₂₋₁₆alkenyl, O—C₁₋₆alkyl and C₁₋₆alkyleneOH.

In an embodiment, Z is O or C(O) and each R¹ is independently selectedfrom OH, Br, Cl, F, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, O—C₁₋₁₂alkyl andC₁₋₁₆alkyleneOH, C(O)C₁₋₁₂alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₃₋₁₈ cycloalkyl,C(O)C₁₋₁₂alkyleneC₃₋₁₈cycloalkyl, C(O)C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,C(O)C₃₋₁₈ heterocycloalkyl, C(O)C₁₋₁₂alkyleneC₃₋₁₈heterocycloalkyl,C(O)C₁₋₁₂alkenyleneC₃₋₁₈ heterocycloalkyl, C(O)C₆₋₁₈ aryl,C(O)C₁₋₁₂alkyleneC₆₋₁₈ aryl, C(O)C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C(O)C₅₋₁₈heteroaryl, C(O)C₁₋₁₂alkyleneC₅₋₁₈heteroaryl andC(O)C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl wherein all alkyl, alkenyl, alkynyl,alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl groups are optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl. In anembodiment, R¹ is selected from OH, Br, Cl, F, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, O—C₁₋₁₂alkyl, C₁₋₁₆alkyleneOH, C(O)C₁₋₁₂alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₁₋₁₂alkenyleneC₃₋₁₈heterocycloalkyl,C(O)C₁₋₁₂alkyleneC₆₋₁₈ heterocycloalkyl, C(O)C₆₋₁₈ aryl,C(O)C₁₋₁₂alkyleneC₆₋₁₈ aryl and C(O)C₂₋₁₆alkenyleneC₆₋₁₈ aryl whereinall alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkylene,heterocycloalkyl, and aryl groups are optionally substituted with one ormore substituents selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl.

In an embodiment, each R¹ is independently selected from OH, Br, Cl, F,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, O—C₁₋₁₂alkyl, C₁₋₁₆alkyleneOH,C(O)C₁₋₁₂alkyleneC₆₋₁₈heterocycloalkyl, C(O)C₁₋₁₂alkenyleneC₃₋₁₈heterocycloalkyl, C(O)C₁₋₁₂alkyl, C(O)C₁₋₁₂alkyleneC₆₋₁₈ aryl,C(O)C₂₋₁₆alkenyleneC₆₋₁₈ aryl, and C(O)C₆₋₁₈ aryl wherein all alkyl,alkenyl, alkylene, alkenylene, alkynyl, heterocycloalkyl, and arylgroups are optionally substituted with one or more substituents selectedfrom OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl and OC₁₋₁₆alkyl.

In an embodiment, one R¹ is selected from C(O)C₁₋₁₂alkyleneC₆₋₁₈aryl andC(O)C₂₋₁₆alkenyleneC₆₋₁₈ aryl, wherein alkylene, alkenylene and arylgroups are optionally substituted with one or more substituents selectedfrom OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl and OC₁₋₆alkyl.

In an embodiment, one R¹ is selected from C(O)C₁₋₁₂alkyl wherein allalkyl groups are optionally substituted with one or more substituentsselected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl and OC₁₋₆alkyl.

In an embodiment, one R¹ is selected fromC(O)C₁₋₁₂alkyleneC₆₋₁₈heterocycloalkyl and C(O)C₁₋₁₂alkenyleneC₆₋₁₈heterocycloalkyl wherein all alkylene, alkenylene, and heterocycloalkylgroups are optionally substituted with one or more substituents selectedfrom OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl and OC₁₋₆alkyl.

In an embodiment, one R¹ is selected from C(O)C₆₋₁₈aryl optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl and OC₁₋₆alkyl.

In an embodiment, the C₃-C₁₈cycloalkyl in R¹ is independently selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl and cyclodecanyl.

In an embodiment, the heterocycloalkyl in R¹ is selecteddihydrobenzofuranyl, benzodioxolyl aziridinyl, oxiranyl, chromanyl,isochromanyl, thiiranyl, oxaxiridinyl, 1,3-dioxolanyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dioxiranyl,azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl,dihydropyranochromenyl, chromenyl, dihydrochromenonyl chromenonyl,chromanonyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, imidazolidinyl, 2-oxopiperdinyl, pyrazolidinyl,2-oxoazepinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl,thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl,tetrahydropyranyl, diazinanyl (e.g, piperazinyl), piperidyl morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl anddiazepanyl.

In an embodiment, the heteroaryl in R¹ is selected from azepinyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,dihydrobenzofuryl, dihydrobenzothienyl, furyl, imidazolidinyl,imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl,2-oxopiperazinyl, 2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl,pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, triazolyl and thienyl.

In an embodiment, each R¹ independently selected from OH, Br, Cl, F,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, O—C₁₋₁₂alkyl andC₁₋₁₆alkyleneOH, C(O)C₁₋₁₂alkyl, C₃₋₁₈cycloalkyl, C₁₋₁₂alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,C₁₋₁₂alkyleneC₃₋₁₈ heterocycloalkyl,C₁₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈ aryl, C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, and C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl whereinall alkyl, alkenyl, alkynyl, alkylene, alkenylene, aryl, cycloalkyl,heteroaryl and heterocycloalkyl groups are optionally substituted withone or more substituents selected from OH, halo, C₁₋₁₂alkyl,C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, andOC₂₋₁₆alkynyl.

In an embodiment, one R¹ is selected from C₃₋₁₈ cycloalkyl,C₁₋₁₂alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, C₁₋₁₂alkyleneC₃₋₁₈heterocycloalkyl, andC₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl wherein all alkyl, alkenyl,alkynyl, alkylene, cycloalkyl and heterocycloalkyl groups are optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, andOC₂₋₁₆alkynyl. In an embodiment, one R¹ is selected fromC₃₋₁₈cycloalkyl, C₁₋₆alkyleneC₃₋₁₈ cycloalkyl,C₂₋₆alkenyleneC₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,C₁₋₆alkyleneC₃₋₁₈heterocycloalkyl, orC₂₋₆alkenyleneC₃₋₁₈heterocycloalkyl wherein all alkyl, alkenyl,alkylene, cycloalkyl and heterocycloalkyl groups are optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, andOC₂₋₁₆alkynyl. In an embodiment, the heterocycloalkyl in R¹ isbenzofurochromenone, dihydropyranochromenyl, chromenyl,dihydrochromenonyl, chromenonyl, chromanonyl dihydrobenzofuranyl,benzodioxolyl, or dithianyl optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl. In anembodiment, one R¹ is benzofurochromenone, dihydropyranochromenyl,chromenyl, dihydrochromenonyl chromenonyl, chromanonyldihydrobenzofuranyl, C₁₋₆alkylenedihydrobenzofuranyl,C₂₋₆alkenylenedihydrobenzofuranyl, benzodioxolyl,C₁₋₆alkylenebenzodioxolyl, C₂₋₆alkenylenebenzodioxolyl, dithianylC₁₋₆alkylenedithianyl, or C₁₋₆alkenylenedithianyl optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₂alkyl,C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₂alkyl, OC₂₋₁₆alkenyl, andOC₂₋₁₆alkynyl. In an embodiment, one R¹ is benzofurochromenone,dihydropyranochromenyl, chromenyl, dihydrochromenonyl, chromenonyl,chromanonyl, dihydrobenzofuranyl, C₂₋₆alkenylenedihydrobenzofuranyl,benzodioxolyl, or dithianyl optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl.

In an embodiment, one R¹ is selected from C₆₋₁₈aryl,C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C₆₋₁₈heteroaryl,C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, and C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl whereinall alkyl, alkenyl, alkynyl, alkylene, aryl, cycloalkyl, heteroaryl andheterocycloalkyl groups are optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆ alkynyl. In an embodiment, one R¹is selected from C₆₋₁₈aryl, C₂₋₆alkyleneC₅₋₁₈heteroaryl,C₂₋₆alkenyleneC₅₋₁₈heteroaryl, C₁₋₆alkyleneC₆₋₁₈aryl andC₁₋₆alkenyleneC₆₋₁₈aryl, wherein all alkyl, alkenyl, alkynyl, alkylene,heteroaryl aryl, groups are optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl andOC₁₋₁₂alkyl. In an embodiment, one R¹ is selected from phenyl,C₂alkylenephenyl and C₂alkenylenephenyl, wherein all alkyl, alkenyl,alkynyl, alkylene and phenyl groups are optionally substituted with oneor more substituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyland OC₁₋₁₂alkyl.

In an embodiment, one R¹ is selected from OH, O₆₋₁₈aryl, andC₅₋₁₈heteroaryl, wherein all alkyl, alkenyl, alkynyl, aryl, and,heteroaryl groups are optionally substituted with one or moresubstituents selected from OH, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, OC₁₋₁₂alkyl,OC₂₋₁₆alkenyl. In an embodiment, when n is greater than 1, specificallywhen n is 2, two R¹ groups are linked together to form a polycyclic ringsystem having 8 or more atoms together with the phenyl ring to whichsaid groups are bonded, and in which one or more carbon atoms in saidpolycyclic ring system is optionally replaced with a heteromoietyselected from NR⁶, O and S, wherein the polycyclic ring system isoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸,C₆₋₁₈aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl,the latter 4 groups being optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, andC₂₋₁₆alkenyl.

In an embodiment, the polycyclic ring system is a bridged polycyclicring system, which is optionally substituted with one or moresubstituents selected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl. In anembodiment, the polycyclic ring system is a spirofused polycyclic ringsystem, which is optionally substituted with one or more substituentsselected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl,OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl. In an embodiment, the polycyclic ringsystem is a fused polycyclic ring system, which is optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, andOC₂₋₁₆alkynyl.

In an embodiment, the polycyclic ring system is selected from apolycyclic cycloalkyl ring system, polycyclic heterocyclyl ring system,a polycyclic heteroaryl ring system and a polycyclic aryl ring system,which are optionally substituted with one or more substituents selectedfrom OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, the polycyclic ringsystem is selected from a polycyclic cycloalkyl ring system, polycyclicheterocyclyl ring system, a polycyclic heteroaryl ring system and apolycyclic aryl ring system, which are optionally substituted with oneor more substituents selected from OH, ═O, halo, C₁₋₁₆alkyl,C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl andOC₂₋₁₆alkynyl.

In an embodiment, the polycyclic ring system is selected from abicyclic, tricyclic and a quadracyclic ring system, which are optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl,C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter4 groups being optionally substituted with one or more substituentsselected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In anembodiment, the polycyclic ring system is selected from a bicyclic,tricyclic and a quadracyclic ring system, which are optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl.

In an embodiment, the polycyclic ring system is a gonanyl (steroidnucleus) which is optionally substituted with one or more substituentsselected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl,OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸,C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, the polycyclic ringsystem is a gonanyl (steroid nucleus) wherein the gonanyl ring system isoptionally substituted with one or more substituents selected from OH,═O, C₁₋₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, and OC₁₋₆alkyl. In anembodiment, two adjacent R¹ groups are linked together to form a gonanylring system, wherein the gonanyl ring system is optionally substitutedwith one or more substituents selected from OH, ═O, C₁₋₆alkyl,C₂₋₁₆alkenyl, C₂₋₆alkynyl, and OC₁₋₆alkyl.

In an embodiment, the polycyclic heteroaryl ring system is selected frombenzofuranyl, isobenzofuranyl, indolyl, isoindolyl, quinolinyl,isoquinolinyl, benzepinyl, carbazolyl, and acridinyl which areoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, the polycyclicheteroaryl ring system is selected from benzofuranyl, isobenzofuranyl,indolyl, isoindolyl, quinolinyl, and isoquinolinyl which are optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl,C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter4 groups being optionally substituted with one or more substituentsselected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, the polycyclic heterocyclyl ring system is abenzofused ring system which is optionally substituted with one or moresubstituents selected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸,C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl,C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl the latter 4 groups beingoptionally substituted with one or more substituents selected from OH,halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, thebenzofused ring system is selected from benzofurochromenone,benzodiozinyl, benzodiozolyl, indenyl, indolinyl, chromenyl,dihydrochromenonyl, chromenonyl, chromanonyl, benzoxazinyl,quinolinonyl, isoquinolinonyl and coumarinyl which are optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸,C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈ heterocycloalkyl, andC₅₋₁₈heteroaryl, the latter 4 groups being optionally substituted withone or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, the benzofused ringsystem is selected from benzofurochromenone, benzodiozinyl,benzodiozolyl, indenyl, indolinyl, chromenyl, dihydrochromenonylchromenonyl, chromanonyl, benzoxazinyl, quinolinonyl and isoquinolinonylwhich are optionally substituted with one or more substituents selectedfrom OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, the benzofused ring system is selected from chromenyl,chromenonyl (chromonyl) and chromanonyl (dihydrochromenonyl) which areoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, the benzofused ringsystem is selected from chromenyl, chromenonyl (chromonyl) andchromanonyl (dihydrochromenonyl) which are optionally substituted withone or more substituents selected from OH, C₁₋₁₆alkyl, OC₁₋₁₆alkyl,C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl,the latter 4 groups being optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, andC₂₋₁₆alkenyl. In an embodiment, the benzofused ring system is selectedfrom chromenyl, chromenonyl (chromonyl) and chromanonyl(dihydrochromenonyl) which are optionally substituted with one or moresubstituents selected from OH, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, C₆₋₁₈aryl,C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter4 groups being optionally substituted with one or more substituentsselected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In anembodiment, the benzofused ring system is selected from chromenonyl(chromonyl) and chromanonyl (dihydrochromenonyl) which are optionallysubstituted with one or more substituents selected from OH, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, C₃₋₁₈heterocycloalkyl, and C₆₋₁₈aryl, the latter two groupsbeing optionally substituted with one or more substituents selected fromOH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, the benzofused ring system is selected from which areoptionally substituted with one or more substituents selected from OH,C₁₋₁₆alkyl, OC₁₋₁₆alkyl, C₃₋₁₈heterocycloalkyl, and C₆₋₁₈aryl the lattertwo groups being optionally substituted with one or more substituentsselected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In anembodiment, the C₃₋₁₈heterocycloalkyl is benzodioxolyl or naphthalenone.In an embodiment, the C₆₋₁₈aryl is phenyl.

Therefore, in an embodiment, the benzofused ring system is a flavonyl,isoflavonyl, flavavonyl or isoflavavonyl, which are optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, thebenzofused ring system is selected from

which are optionally substituted with one or more substituents selectedfrom OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, the benzofused ring system is coumarinyl which isoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, the benzofused ringsystem is coumarinyl which is optionally substituted with one or moresubstituents selected from OH, ═O, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl. In anembodiment, the benzofused ring system is coumarinyl which is optionallysubstituted with one or more substituents selected from OH, C₁₋₁₆alkyl,C₂₋₁₆alkenyl, and OC₁₋₁₆alkyl.

In an embodiment, the polycyclic heterocyclyl ring system is a tricyclicheterocyclyl ring system which is optionally substituted with one ormore substituents selected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl,C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heterocycloalkyl, the latter 4 groupsbeing optionally substituted with one or more substituents selected fromOH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment,the tricyclic heterocyclyl ring system is selected from flourenyl,carbazolyl, dibenzofuranyl, phenoxazinyl, and xanthonyl which areoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₃₋₁₈heterocycloalkyl, the latter 4 groups being optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, thetricyclic heterocyclyl ring system is a xanthonyl which is optionallysubstituted with one or more substituents selected from OH, C₁₋₁₆alkyl,C₂₋₁₆alkenyl, and OC₁₋₁₆alkyl. In an embodiment, the tricyclicheterocyclyl ring system is a xanthonyl which is optionally substitutedwith one or more OH. In an embodiment, the tricyclic heterocyclyl ringis

which is optionally substituted with one or more substituents selectedfrom OH, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, and OC₁₋₁₆alkyl.

In an embodiment, the polycyclic heterocyclyl ring system is atetracyclic heterocyclyl ring system which is optionally substitutedwith one or more substituents selected from OH, ═O, halo, C₁₋₁₆alkyl,C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl,C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heterocycloalkyl, the latter 4 groupsbeing optionally substituted with one or more substituents selected fromOH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment,the tetracyclic heterocyclyl ring system is a benzofurochromenone whichis optionally substituted with one or more substituents selected fromOH, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, and OC₁₋₁₆alkyl. In an embodiment, thetetracyclic heterocyclyl ring system is

which is optionally substituted with one or more substituents selectedfrom OH, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, and OC₁₋₁₆alkyl.

In an embodiment, the polycyclic aryl ring system is selected fromnaphthalenyl, anthracenyl, phenanthrenyl, tetracenyl, chrysenyl,triphenylenyl, pyrenyl, pentacenyl, benzo[a]pyrenyl, corannulenyl,benzo[ghi]perylenyl, coronenyl, ovalenyl and benzo[c]fluorinyl which areoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₃₋₁₈heterocycloalkyl, the latter 4 groups being optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, thepolycyclic aryl ring system is naphthalenyl which is optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl,C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heterocycloalkyl, thelatter 4 groups being optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, andC₂₋₁₆alkenyl. In an embodiment, the polycyclic aryl ring system isnaphthalenyl which is optionally substituted with one or moresubstituents selected from OH, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl,OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C(O)O₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl. In an embodiment, the polycyclic aryl ring system isnaphthalenyl which is optionally substituted with one or more OH.

In an embodiment, when n is greater than 1, specifically when n is 2,two adjacent R¹ groups are linked together to form polycyclic ringsystem having 8 or more atoms together with the phenyl ring to whichsaid groups are bonded, and in which one or more carbon atoms in saidpolycyclic ring system is optionally replaced with a heteromoietyselected from NR⁶, O and S, wherein the polycyclic ring system isoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,OC₂₋₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸,C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈ heterocycloalkyl, andC₃₋₁₈heterocycloalkyl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

Therefore, when n is 2, in an embodiment, the compound of Formula (I)has the following structure

-   -   wherein:    -   the two R¹ groups are linked together to form a polycyclic ring        system having 8 or more atoms together with the phenyl ring to        which said groups are bonded, and in which one or more carbon        atoms in said polycyclic ring system is optionally replaced with        a heteromoiety selected from NR⁶, O and S, wherein the        polycyclic ring system is optionally substituted with one or        more substituents selected from ═O, OH, halo, C₁₋₁₆alkyl,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl,        C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups        being optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and        C₂₋₁₆alkenyl;    -   R² is H,    -   R³, R⁴ and R⁵ are as defined in Formula (I), and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the two R¹ groups are linked together to form apolycyclic ring system having 10 or more atoms together with the carbonatoms to which said groups are bonded, and in which one or more carbonatoms in said polycyclic ring system is optionally replaced with aheteromoiety selected from NR⁶, O and S, wherein the polycyclic ringsystem is optionally substituted with one or more substituents selectedfrom ═O, OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl as described above for the compounds ofFormula (I) above.

In an embodiment, the polycyclic ring system is as described above.

In an embodiment, the compound of Formula (I) is a compound of Formula(I-A)

-   -   wherein:    -   each R¹ is independently selected from OH, halo, CN, NO₂, COOH,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈        cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl,        C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈aryl,        C₂₋₁₆alkynyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyl, Z—C₂₋₁₆alkenyl,        Z—C₂₋₁₆alkynyl, Z—C₃₋₁₈cycloalkyl,        Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈        cycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl,        Z—C₃₋₁₈heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, Z—C₆₋₁₈aryl, Z—C₁₋₁₆alkyleneC₆₋₁₈aryl,        Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkynyleneC₆₋₁₈aryl,        Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,        Z—C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl, and        Z—C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,    -   wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl heterocycloalkyl, aryl, and heteroaryl        groups are optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; or    -   when m is greater than 1, two R¹ groups are linked together to        form a polycyclic ring system having 8 or more atoms together        with the phenyl ring to which said groups are bonded, and in        which one or more carbon atoms in said polycyclic ring system is        optionally replaced with a heteromoiety selected from NR⁶, O and        S, wherein the polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,        OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸,        C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl,        C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the        latter 4 groups being optionally substituted with one or more        substituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl,        and C₂₋₁₆alkenyl; and    -   R², R³, R⁴ and R⁵ are as defined in Formula (I),    -   m is an integer selected from 0 to 3; and    -   all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, each R¹ in the compound of Formula (I-A) isindependently selected from OH, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₆₋₁₈aryl,C₁₋₁₂alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,Z—C₁₋₁₆alkyleneC₆₋₁₈aryl, Z—C₆₋₁₈aryl, Z—C₂₋₁₆alkenyleneC₆₋₁₈ aryl,Z—C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl, Z—C₅₋₁₈heteroaryl,Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,and Z—C₂₋₁₆alkenyleneC₆₋₁₈heteroaryl, wherein all alkyl, alkenyl,alkynyl, alkylene, alkenylene, aryl, heterocycloalkyl and heteroarylgroups are optionally substituted with one or more substituents selectedfrom OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, and OC₁₋₁₂alkyl.

In an embodiment, R¹ in the compound of Formula (I-A) is selected fromC₁₋₁₂alkyl and C₂₋₁₆alkenyl. In an embodiment, m is 1 and R¹ in thecompound of Formula (I-A) is C₁₋₆alkyl which is in a position meta toeach of the hydroxy groups. In an embodiment, m is 1, and R¹ in thecompound of Formula (I-A) is C₁₋₁₂alkyl. In an embodiment, m is 1 and R¹in the compound of Formula (I-A) is C₁₋₁₂alkyl which is in a positionmeta to each of the hydroxy groups. In an embodiment, m is 1 and R¹ inthe compound of Formula (I-A) is pentyl which is in a position meta toeach of the hydroxy groups.

In an embodiment, each R¹ in the compound of Formula (I-A) isindependently selected from OH, C₁₋₁₂alkyl, C₂₋₁₆alkenyl,C₁₋₁₂alkyleneC₆₋₁₈ aryl, and C₂₋₁₆alkenyleneC₆₋₁₈ aryl, wherein allalkyl, alkenyl, alkylene, alkenylene and aryl groups are optionallysubstituted with one to three substituents selected from OH, C₁₋₁₂alkyl,C₂₋₁₆alkenyl, and OC₁₋₁₂alkyl.

In an embodiment, one R¹ in the compound of Formula (I-A) is selectedfrom C₁₋₆alkyleneC₆₋₁₀aryl and C₂₋₆alkenyleneC₆₋₁₀ aryl, wherein allalkylene, alkenylene and aryl groups are optionally substituted with oneto three substituents selected from OH, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, andOC₁₋₁₂alkyl.

In an embodiment, m is 1, and R¹ in the compound of Formula (I-A) isselected from C₂alkylenephenyl and C₂alkenylenephenyl, wherein thephenyl groups are optionally substituted with one to three substituentsselected from OH and C₂₋₁₆alkenyl. In an embodiment, m is 1, and R¹ inthe compound of Formula (I-A) is selected from C₂alkylenephenyl andC₂alkenylenephenyl, wherein the phenyl groups are optionally substitutedwith one to three substituents selected from OH and C₂₋₁₆alkenyl, andwherein R¹ is in a position meta to each of the hydroxy groups.Therefore, in an embodiment, the compound of Formula (I-A) is

wherein the phenyl group is optionally substituted with one to threesubstituents selected from OH and C₂₋₁₆alkenyl.

In an embodiment, each R¹ in the compound of Formula (I-A) isindependently selected from OH, C₂₋₁₆alkenyl, Z—C₁₋₁₆alkyl, Z—C₆₋₁₈aryl, Z—C₁₋₁₆alkyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkenyleneC₆₋₁₈ aryl,Z—C₁₋₁₆alkyleneC₆₋₁₈heterocycloalkyl,Z—C₁₋₁₆alkenyleneC₆₋₁₈heterocycloalkyl, Z—C₅₋₁₈ heteroaryl,Z—C₁₋₁₆alkyleneC₅₋₁₈ heteroaryl, and Z—C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl,wherein all alkyl, alkenyl, alkylene, alkenylene, aryl, heterocycloalkyland heteroaryl groups are optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₂alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₁₋₁₂alkyl.

In an embodiment, Z is C(O) or O and one R¹ in the compound of Formula(I-A) is independently selected from C(O)C₁₋₁₆alkyl, C(O)C₆₋₁₈ aryl,C(O)C₁₋₁₆alkyleneC₆₋₁₈aryl, C(O)C₂₋₁₆alkenyleneC₆₋₁₈ aryl,C(O)C₁₋₁₆alkyleneC₆₋₁₈heterocycloalkyl,C(O)C₁₋₁₆alkenyleneC₆₋₁₈heterocycloalkyl, C(O)C₅₋₁₈ heteroaryl,C(O)C₁₋₁₆alkyleneC₅₋₁₈ heteroaryl, andC(O)C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, wherein all alkyl, alkylene,alkenylene, aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, and OC₁₋₁₂alkyl.

In an embodiment, one R¹ in the compound of Formula (I-A) isC(O)C₁₋₁₆alkyl.

In an embodiment, one R¹ in the compound of Formula (I-A) is selectedfrom C(O)C₁₋₆alkyleneC₆₋₁₈ aryl, C(O)C₂₋₆alkenyleneC₆₋₁₀ aryl,C(O)C₁₋₆alkyleneC₃₋₁₀heterocycloalkyl,C(O)C₂₋₆alkenyleneC₅₋₁₀heterocycloalkyl,C(O)C₁₋₆alkyleneC₅₋₁₀heteroaryl, and C(O)C₂₋₁₆alkenyleneC₅₋₁₀heteroaryl, wherein all alkylene, alkenylene, aryl, heterocycloalkyl andheteroaryl groups are optionally substituted with one or moresubstituents selected from OH, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, andOC₁₋₁₂alkyl.

In an embodiment, one R¹ in the compound of Formula (I-A) is selectedfrom C(O)C₂₋₆alkenyleneC₆₋₁₀aryl, andC(O)C₂₋₆alkenyleneC₃₋₁₀heterocycloalkyl, wherein all, alkenylene, aryl,and heterocycloalkyl groups are optionally substituted with one or moresubstituents selected from OH, C₁₋₁₂alkyl, and C₂₋₁₆alkenyl.

In an embodiment, one R¹ in the compound of Formula (I-A) is selectedfrom C(O)C₂alkenylenephenyl, and C(O)C₂alkenyleneC₁₀heterocycloalkyl,wherein all alkenylene, phenyl, and heterocycloalkyl groups areoptionally substituted with one or more substituents selected from OH,C₁₋₄alkyl, and C₂₋₆alkenyl.

In an embodiment, one R¹ in the compound of Formula (I-A) isC₅₋₁₀heteroaryl wherein the heteroaryl groups are optionally substitutedwith one or two OH. In an embodiment, the C₅₋₁₀heteroaryl in R¹ isbenzofuran.

In an embodiment, when m greater than 1, two adjacent R¹ groups in thecompound of Formula (I-A) are linked together to form a polycyclic ringsystem having 10 or more atoms together with the phenyl ring to whichsaid groups are bonded, and in which one or more carbon atoms in saidpolycyclic ring system is optionally replaced with a heteromoietyselected from NR⁶, O and S, wherein the polycyclic ring system isoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₃₋₁₈heterocycloalkyl, the latter 4 groups being optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl. In an embodiment, thepolycyclic ring system is substituted with C₂₋₁₆alkenyl and furtheroptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₃₋₁₈heterocycloalkyl, the latter 4 groups being optionallysubstituted with one or more substituents selected from OH, halo,C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, two adjacent R¹ groups in the compound of Formula(I-A) are linked together to form a bicyclic system having 10 atomstogether with the phenyl ring to which said groups are bonded, and inwhich one or more carbon atoms in said bicyclic ring system isoptionally replaced with a heteromoiety selected from O, wherein thepolycyclic ring system is optionally substituted with one or moresubstituents selected from OH, ═O, C₁₋₆alkyl, OC₁₋₆alkyl, C₆₋₁₈ arylsubstituted with one or more substituents selected from OH, C₁₋₆alkyl,OC₁₋₆alkyl, and C₂₋₁₆alkenyl, and C₃₋₁₈heterocycloalkyl substituted withone or more substituents selected from OH, C₁₋₆alkyl, OC₁₋₆alkyl, andC₂₋₁₆alkenyl.

In an embodiment, the bicyclic system is substituted with C₂₋₁₆alkenyland further is optionally substituted with one or more substituentsselected from OH, ═O, C₁₋₆alkyl, OC₁₋₆alkyl, C₆₋₁₈ aryl substituted withone or more substituents selected from OH, C₁₋₆alkyl, OC₁₋₆alkyl, andC₂₋₁₆alkenyl, and C₃₋₁₈heterocycloalkyl substituted with one or moresubstituents selected from OH, C₁₋₆alkyl, OC₁₋₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, two adjacent R¹ groups in the compound of Formula(I-A) are linked together to form, with the phenyl ring to which theyare attached, a chromanone or a chromenone, which is optionallysubstituted with one or more substituents selected from OH, ═O,OC₁₋₆alkyl, phenyl substituted with one or more substituents selectedfrom OH, C₁₋₆alkyl, OC₁₋₆alkyl, and C₂₋₁₆alkenyl, andC₁₀heterocycloalkyl substituted with one or more substituents selectedfrom OH and C₁₋₆alkyl]. In an embodiment, the chromanone or chromenoneis substituted with C₂₋₁₆alkenyl and further optionally substituted withone or more substituents selected from OH, ═O, OC₁₋₆alkyl, phenylsubstituted with one or more substituents selected from OH, C₁₋₆alkyl,OC₁₋₆alkyl, and C₂₋₁₆alkenyl, and C₁₀heterocycloalkyl substituted withone or more substituents selected from OH and C₁₋₆alkyl. In anembodiment, two adjacent R¹ groups in the compound of Formula (I-A) arelinked together to form, with the phenyl ring to which they areattached, a chroman-4-one (dihydrochromen-4-one) or a chromen-4-one,which is optionally substituted with one or more substituents selectedfrom OH, ═O, OC₁₋₆alkyl, and phenyl substituted with one or moresubstituents selected from OH, C₁₋₆alkyl, OC₁₋₆alkyl, and C₂₋₁₆alkenyl.In an embodiment, the chroman-4-one or a chromen-4-one is substitutedwith C₂₋₁₆alkenyl and further optionally substituted with one or moresubstituents selected from OH, ═O, OC₁₋₆alkyl, and phenyl substitutedwith one or more substituents selected from OH, C₁₋₆alkyl, OC₁₋₆alkyl,and C₂₋₁₆alkenyl.

In an embodiment, two adjacent R¹ groups in the compound of Formula(I-A) are linked together to form, with the phenyl ring to which theyare attached, a chroman-4-one or a chromen-4-one, which is optionallysubstituted with one or more substituents selected from OH, ═O,OC₁₋₆alkyl, and phenyl substituted with one or more substituentsselected from OH, C₁₋₆alkyl, OC₁₋₆alkyl, and C₂₋₁₆alkenyl.

Therefore, in an embodiment, two adjacent R¹ groups in the compound ofFormula (I-A) are linked together to form, with the phenyl ring to whichthey are attached, a flavonol, isoflavonol, flavavonol or isoflavavonolwhich is optionally substituted with one or more substituents selectedfrom OH, ═O, OC₁₋₆alkyl, and phenyl substituted with one or moresubstituents selected from OH, C₁₋₆alkyl, OC₁₋₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, two adjacent R¹ groups in the compound of Formula(I-A) are linked together to form, with the phenyl ring to which theyare attached, a polycyclic ring system having 14 or more atoms togetherwith the two adjacent carbon atoms to which said groups are bonded, andin which one or more carbon atoms in said polycyclic ring system isoptionally replaced with a heteromoiety that is O, wherein thepolycyclic ring system is optionally substituted with one or more OH,═O, and C₂₋₁₆alkenyl. In an embodiment, polycyclic ring system having 14or more atoms is substituted with C₂₋₁₆alkenyl and further optionallysubstituted with one or more substituents selected from OH, ═O, andC₂₋₁₆alkenyl.

In an embodiment, two adjacent R¹ groups in the compound of Formula(I-A) are linked together to form, with the phenyl ring to which theyare attached, a xanthone, wherein the xanthone is optionally substitutedwith one or more OH, ═O and C₂₋₁₆alkenyl. In an embodiment, the xanthoneis substituted with C₂₋₁₆alkenyl and further optionally substituted withone or more substituents selected from OH, ═O, and C₂₋₁₆alkenyl.

In an embodiment, two adjacent R¹ groups in the compound of Formula(I-A) are linked together to form, with the phenyl ring to which theyare attached, a xanthone, wherein the xanthone is optionally substitutedwith one or more OH.

In an embodiment, R³ in the compounds of Formula (I), and (I-A) isselected from H, CH₃ and CH₂CH₃. In an embodiment, R³ is selected from Hand CH₃.

In an embodiment, R⁴ in the compounds of Formula (I) and (I-A) isselected from H, CH₃, CH₂CH₃, C₆₋₁₀aryl, C₁₋₆alkyleneC₆₋₁₈aryl, C₅₋₁₀heteroaryl, and C₂₋₆alkyleneC₅₋₁₀heteroaryl. In an embodiment, R⁴ isselected from H, CH₃, CH₂CH₃, phenyl, and C₁₋₆alkylenephenyl. In anembodiment, R⁴ is selected from H, CH₃, and phenyl.

In an embodiment, R⁵ in the compounds of Formula (I) and (I-A) isselected from H, C₁₋₂₀alkyl, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl, C₃₋₁₈cycloalkyl, C₁₋₁₀alkyleneC₃₋₁₈ cycloalkyl,C₂₋₁₀alkenyleneC₃₋₁₈cycloalkyl, C₂₋₁₀alkynyleneC₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, C₁₋₁₀alkyleneC₃₋₁₈heterocycloalkyl,C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,C₂₋₁₀alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₀aryl, C₁₋₁₀alkyleneC₆₋₁₀aryl;C₂₋₁₀alkenyleneC₆₋₁₀aryl, C₂₋₁₀alkynyleneC₆₋₁₀aryl, C₅₋₁₀heteroaryl,C₂₋₁₀alkyleneC₅₋₁₀ heteroaryl, C₂₋₀₆alkenyleneC₅₋₁₀heteroaryl, andC₂₋₁₀alkynyleneC₅₋₁₈heteroaryl, wherein all cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more substituents selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl,C₂₋₁₆alkenyl, C₂₋₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₆alkynyl,C₁₋₁₆alkyleneOR⁹ C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹, SO₃C₁₋₁₆alkyl,SO₃C₆₋₁₆aryl, and SO₃C₅₋₁₈heteroaryl substituted with C₁₋₁₆alkyl.

In an embodiment, R⁵ in the compounds of Formula (I), and (I-A) isselected from H, C₁₋₁₀alkyl, C₂₋₂₀alkenyl, and C₆₋₁₀aryl, wherein arylis optionally substituted with one or more substituents selected fromOH, NO₂, CN, F, Cl, Br, C₁₋₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,OC₁₋₁₆alkyl and SO₃C₁₋₆alkyl.

In an embodiment, R⁵ in the compounds of Formula (I), and (I-A) isselected from H, C₂₋₂₀alkenyl, and phenyl, wherein phenyl is optionallysubstituted with one or more substituents selected from OH, NO₂, CN, F,Cl, Br, CH₃, CH₂CH₃, C₂₋₁₆alkenyl, OC₁₋₆alkyl and SO₃C₁₋₆alkyl.

In an embodiment, R⁵ in the compounds of Formula (I), and (I-A) isphenyl. In an embodiment, R⁵ is phenyl which is substituted with one ormore substituents selected from OH, NO₂, F, Cl, Br, CH₃, OC₁₋₆alkyl andSO₃CH₃.

In an embodiment, R⁴ and R⁵ in the compound of Formula (I), and (I-A)are both phenyl. In an embodiment, R⁴ is H and R⁵ is phenyl. In anembodiment, R⁴ is H and R⁵ is phenyl which is substituted with one ormore substituents selected from OH, NO₂, F, Cl, Br, CH₃, OC₁₋₆alkyl andSO₃CH₃.

In an embodiment, R⁵ in the compound of Formula (I), and (I-A) is H. Inan embodiment, R⁵ is C₁₋₁₀alkyl. In an embodiment, R⁵ is selected fromCH₃ and CH₂CH₃. In an embodiment, R⁵ is CH₃.

In an embodiment, R⁵ in the compound of Formula (I), and (I-A) isC₂₋₂₀alkenyl. In an embodiment, R⁵ is selected from

wherein

represents a point of covalent attachment. In an embodiment, R⁵ is

wherein

represents a point of covalent attachment. In an embodiment, R⁴ and R⁵in the compound of Formula (I) and (I-A) are both CH₃. In an embodiment,R⁴ is CH₃ and R⁵ is

wherein

represents a point of covalent attachment.

Therefore, in an embodiment, the compound of Formula (I), and (I-A)comprises a prenyl functional group

or repeating prenyl functional groups such as prenyl, geranyl, phytyl,farnesyl, or neryl wherein

represents a point of covalent attachment. Therefore, in an embodiment,the compound of Formula (I), and (I-A) is an ortho-prenylated hydroxyaryl compound or ortho-polyprenylated hydroxy aryl compound also knownas ortho-prenylated phenolics or ortho-polyprenylated phenolics.

In an embodiment, any two of R², R³, R⁴ and R⁵ in the compound ofFormula (I) or (I-A) are linked together to form an unsubstituted orsubstituted monocyclic or polycyclic ring system having 4 or more atomstogether with the carbon atoms to which said any two of R², R³, R⁴ andR⁵ are bonded, wherein the monocyclic or polycyclic ring system isoptionally substituted with one or more substituents selected ═O, OH,halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl;

In an embodiment, R² and R⁵ in the compound of Formula (I) or (I-A) arelinked together to form an unsubstituted or substituted monocyclic ringsystem having 6 or more atoms together with the carbon atoms to whichsaid R² and R⁵ are bonded, wherein the monocyclic ring system isoptionally substituted with one or more substituents selected OH,C₁₋₁₆alkyl, and C₂₋₁₆alkenyl.

In an embodiment, R² and R⁵ in the compound of Formula (I-A) are linkedtogether to form an unsubstituted or substituted monocyclic ring systemhaving 6 or more atoms together with the carbon atoms to which said R²and R⁵ are bonded, wherein the monocyclic ring system is optionallysubstituted with one or more substituents selected OH, C₁₋₁₆alkyl, andC₂₋₁₆alkenyl. In an embodiment, R² and R⁵ in the compound of Formula(I-A) are linked together to form isopiperitenol. In an embodiment, R²and R⁵ in the compound of Formula (I-A) are linked together to form

wherein

represents a point of covalent attachment.

In an embodiment, the compound of Formula (I) is selected from acannabinoid. In an embodiment, the cannabinoid is selected fromcannabidiol, cannabidivarin, cannabigerol, cannabigerorcin andcannabigerivarin. In an embodiment, the compound of Formula (I) iscannabidiol. In an embodiment, the compound of Formula (I) is selectedfrom, cannabidivarin, cannabigerol, grifolin, cannabigerorcin,piperogalin and cannabigerivarin. In an embodiment, the compound ofFormula (I) is selected from cannabigerol, piperogalin and grifolin.

In R² and R⁵ in the compound of Formula (I-A) are linked together toform isopiperitenol and the compound of Formula (I-A) is cannabidiol.

In an embodiment, the compound of Formula (I), and (I-A) is a naturalcompound. In an embodiment, the compound of Formula (I), and (I-A) is anatural occurring phenolic compound. In an embodiment, the compound ofFormula (I) and (I-A) is selected from a class of compound comprisingcannabinoids, phenols, resorcinols, chalconoids, moracins, stilbenoidd,polycyclic aromatics, flavanonols, isoflavanonols, flavonols,isoflavonols, chromones, coumarins and xanthones.

In an embodiment, the compound of Formula (I), and (I-A) comprises aprenyl functional group

or repeating prenyl functional groups, therefore the compound of Formula(I) and (I-A) is selected class of compound comprising prenylated orpolyprenylated cannabinoids, phenols, resorcinols, chalconoids,moracins, stilbenoidd, polycyclic aromatics, flavanonols,isoflavanonols, flavonols, isoflavonols, chromones, coumarins andxanthones.

It would be appreciated by a person skilled in the art R¹ in a compoundof Formula (II) and R², R³, R⁴ and R⁵ for a compound of Formula (II)would correspond to R¹, R², R³, R⁴ and R⁵ selected for the compound ofFormula (I).

It would also be appreciated by a person skilled in the art that thecompounds of Formula (I) can be further reacted to form furtherscaffolds of interest. For example, exemplary compounds of Formula (I),cannabidiol and cannabidivarin, can be further cyclized to formtetrahydrocannabinol and tetrahydrocannabivarin, respectively.Conditions for cyclization would be known a person skilled in the art.

In an embodiment, the compound of Formula (I) is selected from thecompounds listed below:

Compound I.D Structure I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10 

I-11 

I-12 

I-13 

I-14 

I-15 

I-16 

I-17 

I-18 

I-19 

I-20 

I-21 

I-22 

I-23 

I-24 

I-25 

I-26 

I-27 

I-28 

I-29 

I-30 

I-31 

I-32 

I-33 

I-34 

I-35 

I-36 

I-37 

I-38 

I-39 

I-40 

I-41 

I-42 

I-43 

I-44 

I-45 

I-46 

I-47 

I-48 

I-49 

I-51 

I-52 

I-53 

I-54 

I-55 

I-56 

I-57 

I-58 

I-59 

I-60 

I-61 

I-62 

I-63 

I-64 

I-65 

I-66 

I-67 

I-68 

I-69 

I-70 

I-71 

I-72 

I-73 

I-74 

I-75 

I-76 

I-77 

I-78 

I-79 

I-80 

I-81 

I-82 

I-83 

I-84 

I-85 

I-86 

I-87 

I-88 

I-89 

I-90 

I-91 

I-92 

I-93 

I-94 

I-95 

I-96 

I-97 

I-98 

I-99 

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

In an embodiment, the compound of Formula (I) is naturally occurringcompound selected from the compounds I-1 to I-4, I-58 to I-124, I-31 toI-167.

In an embodiment, when n is greater than 1, the compound of Formula (I)is a compound selected from the compounds listed below:

Compound I.D Structure I-10

I-11

I-23

I-24

I-25

I-53

I-54

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-117

I-118

I-119

I-120

I-121

I-122

I-129

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-159

I-162

I-164

In an embodiment, the forming of the compound of Formula (I) or (I-A)comprise mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent undercontinuous flow reaction conditions using for example continuousprocessors. Continuous flow processors comprise a combination of mixingand conveying means that allow the reactants to flow into or through amixing means, react to form products and allow the products to flow outof the mixing means for isolation and purification on a continuousbasis. In the mixing and conveying means, the reaction conditions (suchas temperature and pressure) can be controlled. Such continuous flowprocessors are well known in the art.

In an embodiment, the forming of the compound of Formula (I) or (I-A)comprise mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent under batchreaction conditions.

In an embodiment, when forming a mono ortho-allylated compound ofFormula I, the forming of the compound of Formula (I) or (I-A) furthercomprises mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent with theaddition of excess amounts of the compound of Formula (II). In anembodiment, the forming of the compound of Formula (I) or (I-A)comprises mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent with theaddition of, for example, about 1.1 to about 5, about 1.1 to about 4,about 1.1 to about 3, 1.5 to about 4, about 1.5 to about 5, about 2 toabout 5, about 2 to about 4, about 3 to about 4, or about 1.5 to about 3molar equivalents of the hydroxy aryl compound relative to the amount ofthe allylic alcohol. In an embodiment, the forming of the compound ofFormula (I) or (I-A) comprises mixing the compound of Formula (II), thecompound of Formula (III) and the aluminum compound in the non-proticsolvent with the addition of, for example, about 1 to about 5, about 1to about 4, about 1 to about 3, or about 1.5 to about 3 molarequivalents the compound of Formula (II) relative to the amount of thecompound of Formula (III). In an embodiment, the forming of the compoundof Formula (I) or (I-A) comprise mixing the compound of Formula (II),the compound of Formula (III) and the aluminum compound in thenon-protic solvent with about 1.5 molar equivalents of the compound ofFormula (II) relative to the amount of the compound of Formula (III).

The Applicants have shown that using greater than 1.5 molar equivalentsof the compound of Formula (II) relative to the amount of the compoundof Formula (III) provides improved yields of the compound of Formula (I)or (I-A). Therefore, in an embodiment, the forming of the compound ofFormula (I) or (I-A) further comprise mixing the compound of Formula(II), the compound of Formula (III) and the aluminum compound in thenon-protic solvent with 1.5 to about 4, about 1.5 to about 5, about 2 toabout 5, about 2 to about 4, or about 3 to about 4 molar equivalents ofthe compound of Formula (II) relative to the amount of the compound ofFormula (III). in an embodiment, the forming of the compound of Formula(I) or (I-A) further comprise mixing the compound of Formula (II), thecompound of Formula (III) and the aluminum compound in the non-proticsolvent with about 3 to about 4 molar equivalents of the compound ofFormula (II) relative to the amount of the compound of Formula (III).

In an embodiment, when forming a mono ortho-allylated hydroxy arylcompound, the forming of the compound of Formula (I) or (I-A) furthercomprises mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent with about 1.5to about 4, about 1.5 to about 5, about 2 to about 5, about 2 to about4, or about 3 to about 4 molar equivalents of compound of Formula (II)relative to the amount of the compound of Formula (III). In anembodiment, the forming of the compound of Formula (I) or (I-A) furthercomprises mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent with about 3to about 4 molar equivalents of the compound of Formula (II) relative tothe amount of the compound of Formula (III).

In an embodiment, when it is desired to add additional allyl groups tothe compound of Formula (I) or (I-A) (i.e. a polyallylated hydroxy arylcompound such as a di-, tri- and tetra-allylated hydroxy aryl compoundsof Formula I or I-A) the forming of the compound of Formula (I) or (I-A)comprises mixing the compound of Formula (II), the compound of Formula(III) and the aluminum compound in the non-protic solvent with theaddition of, for example, about 1.1 to about 5, about 1.1 to about 4,about 1.1 to about 3, 1.5 to about 4, about 1.5 to about 5, about 2 toabout 5, about 2 to about 4, about 3 to about 4, or about 1.5 to about 3molar equivalents the compound of Formula (III) relative to the amountof the compound of Formula (II). In an embodiment, the forming of thecompound of Formula (I) or (I-A) comprises mixing the compound ofFormula (II), the compound of Formula (III) and the aluminum compound inthe non-protic solvent with the addition of, for example, about 3 toabout 4, about 3 to about 5, or about 4 to about 5 molar equivalents thecompound of Formula (III) relative to the amount of the compound ofFormula (II).

In an embodiment, the forming of the compound of Formula (I) or (I-A)further comprise mixing the compound of Formula (II), the compound ofFormula (III) and the aluminum compound in the non-protic solvent withthe addition of alumina in the amount of about 1 g to about 3 g, about1.5 g to about 3 g, or about 1.5 g to about 2 g per 1 mmol of thecompound of Formula (III). In an embodiment, the forming of the compoundof Formula (I) or (I-A) comprise mixing the compound of Formula (II),the compound of Formula (III) and the aluminum compound in thenon-protic solvent with the addition of aluminum compound in the amountof about 2 g per 1 mmol of the compound of Formula II).

In an embodiment, the aluminum compound is alumina. In an embodiment,the alumina is acidic alumina. In an embodiment, the acidic alumina, hasa pH of less than about 6.5, about 6, about 5.5, about 5.0, about 4.5 orabout 4.0. In an embodiment, the alumina, has a pH of less than about5.5, about 5.0, about 4.5 or about 4.0. In an embodiment, the alumina,has a pH of about 4.5.

In an embodiment, the alumina is basic alumina. In an embodiment, thebasic alumina, has a pH of greater than about 7.5, about 8, about 8.5,about 9.0, about 9.5, about 10 or about 10.5. In an embodiment, thebasic alumina has a pH of greater than about 9.0, about 9.5, about 10 orabout 10.5. In an embodiment, the basic alumina has a pH of about 10.

In an embodiment, the alumina is neutral alumina. In an embodiment, theneutral alumina has a pH of about 7.

In an embodiment, the forming of the compound of Formula (I) or (I-A)further comprise mixing the compound of Formula (II), the compound ofFormula (III) and the aluminum compound in the non-protic solvent toform a reaction mixture and heating the reaction mixture In anembodiment, the forming of the compound of Formula (I) or (I-A) comprisemixing the compound of Formula (II), the compound of Formula (III) andthe aluminum compound in the non-protic solvent to form a reactionmixture and heating the reaction mixture to the boiling point (refluxingtemperature) of the solvent. In an embodiment, the forming of thecompound of Formula (I) or (I-A) comprise mixing the compound of Formula(II), the compound of Formula (III) and the aluminum compound in DCE toform a reaction mixture and heating the reaction mixture to about 40° C.to about 83° C., about 60° C. to about 83° C., about 70° C. to about 83°C., or about 83° C.

In an embodiment, the forming of the compound of Formula (I) or (I-A)further comprises mixing the compound of Formula (II), the compound ofFormula (III) and the aluminum compound in the non-protic solvent toform a reaction mixture, and heating the reaction mixture for about 4hours to about 24 hours, about 6 hours to about 24 hours, or about 12hours to 24 hours.

In an embodiment, the forming of the compound of Formula (I) or (I-A)further comprises mixing the compound of Formula (II), the compound ofFormula (III) and the aluminum compound in the non-protic solvent toform a reaction mixture, and heating the reaction mixture at therefluxing temperature of the solvent for about 24 hours.

In an embodiment, the forming of the compound of Formula (I) or (I-A)further comprises mixing the compound of Formula (II), the compound ofFormula (III) and the aluminum compound in the non-protic solvent toform a reaction mixture and heating the reaction mixture under microwavesynthesis conditions. Therefore, in an embodiment, the forming of thecompound of Formula (I) or (I-A) further comprises mixing the compoundof Formula (II), the compound of Formula (III) and the aluminum compoundin the non-protic solvent to form a reaction mixture and heating thereaction mixture using microwave radiation. In an embodiment, themicrowave synthesis conditions comprise heating the reaction mixture ina microwave reactor. In an embodiment, the microwave synthesisconditions comprise heating the reaction mixture in a microwave reactorto about 100° C. to about 175° C., about 125° C. to about 175° C., orabout 150° C.

In an embodiment, after heating, the reaction mixture is cooled andfiltered through a filter agent, such as Celite® or silica, and thefiltrate is concentrated for example, by evapouration such asrotoevapouration, to provide a crude product that comprises the compoundof Formula (I) or (I-A). In an embodiment, the crude product is thenpurified using chromatography such as column chromatography using asuitable solvent or mixture of solvents, or any other known purificationmethod.

In an embodiment, the column chromatography is flash columnchromatography. In an embodiment, the suitable mixture of solvents forcolumn chromatography is ethyl acetate and hexane.

In an embodiment, the crude product is purified by crystallization. Inan embodiment, the crude product is purified by crystallization withoutthe use of chromatography. In an embodiment, the crude product iscrystallized using hexane, hexanes, heptane, heptanes, cyclohexane,toluene, xylene and the like. In an embodiment, the crude product is acrude ortho-allylated cannabinoid and the crude product is crystallizedusing hexane, hexanes, heptane, heptanes, or cyclohexane. In anembodiment, the crude product is a crude ortho-allylated cannabinoid andthe crude product is crystallized with heptane.

In an embodiment, the crude product is purified by distillation. In anembodiment, the crude product is purified by distillation without theuse of chromatography.

In an embodiment, the crude product is a crude ortho-allylatedcannabinoid and the crude product is purified by distillation.

In an embodiment, the process of the application can be performedconsecutively such that the compound of Formula (I) or (I-A) formed froma first process of the application is used as the compound of Formula(II) in a subsequent process of the application. Accordingly, in theembodiment, the compound of Formula (II) compound is the compound ofFormula (I) formed by a process of the application described above.

In an embodiment, the process provides the compound of Formula (I) or(I-A) as the as the major product of the process. In an embodiment, theprocess provides the compound of Formula (I) or (I-A) in a yield ofgreater than about 15%, about 20%, about 25%, about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90% or about 95%. In anembodiment, the process provides the compound of Formula (I) or (I-A) ina yield of greater an about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90% or about 95%. In an embodiment, theprocess provides the compound o Formula (I) or (I-A), in a yield ofgreater an about 70%, about 75%, about 80%, about 85%, about 90% orabout 95%.

The Applicants have shown that the compound of Formula (I) can be formedby reacting the compound of Formula (II) with a compound of Formula(III) in the presence of alumina and further additives includingdehydrating reagents such as and magnesium sulfate and/or various acids.Therefore, in an embodiment, the process of the application comprisesreacting the compound of Formula (II) with a compound of Formula (III)in the presence of alumina and a dehydrating agent and in a non-proticsolvent to form the compound of Formula (I).

Accordingly, the application further includes a process for preparing acompound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in the presence of alumina and a dehydrating agent and in a non-proticsolvent to form the compound of Formula (I),

-   -   wherein:    -   each R¹ is independently selected from OH, halo, CN, NO₂, COOH,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈        cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        cycloalkyl, C₃₋₁₈heterocycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl,        C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈aryl,        C₂₋₁₆alkynyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyl, Z—C₂₋₁₆alkenyl,        Z—C₂₋₁₆alkynyl, Z—C₅₋₁₈ cycloalkyl,        Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈        cycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl,        Z—C₃₋₁₈heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, Z—C₆₋₁₈aryl, Z—C₁₋₁₆alkyleneC₆₋₁₈aryl,        Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkynyleneC₆₋₁₈aryl,        Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,        Z—C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl, and        Z—C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,    -   wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl heterocycloalkyl, aryl, and heteroaryl        groups are optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; or    -   when n is greater than 1, two R¹ groups are linked together to        form a polycyclic ring system having 8 or more atoms together        with the phenyl ring to which said groups are bonded, and in        which one or more carbon atoms in said polycyclic ring system is        optionally replaced with a heteromoiety selected from NR⁶, O and        S, wherein the polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,        C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl,        C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heteroaryl, the latter 4 groups        being optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and        C₂₋₁₆alkenyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is H,    -   R³ is selected from H and C₁₋₆alkyl,    -   R⁴ is selected from H, C₁₋₆alkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₅₋₁₈ heteroaryl, and        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl;    -   R⁵ is selected from H, C₁₋₂₆alkyl, C₂₋₂₆alkenyl, C₂₋₂₆alkynyl,        C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈cycloalkyl,        C₃₋₁₈ heterocycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        16alkenyleneC₃₋₁₈ heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, C₆₋₁₈aryl, C₁₋₁₆alkyleneC₆₋₁₈ aryl,        C₂₋₁₆alkenyleneC₆₋₁₈aryl, C₂₋₁₆alkynyleneC₆₋₁₈aryl,        C₅₋₁₈heteroaryl, C₂₋₁₆alkyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,        wherein all cycloalkyl, heterocycloalkyl, aryl and heteroaryl        are optionally substituted with one or more substituents        selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,        C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁹        C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹, SO₃C₁₋₁₆alkyl,        SO₃C₆₋₁₆aryl, and SO₃C₅₋₁₈ heteroaryl substituted with        C₁₋₁₆alkyl; or any two of R², R³, R⁴ and R⁵ are linked together        to form an unsubstituted or substituted monocyclic or polycyclic        ring system having 4 or more atoms together with the carbon        atoms to which said any two of R², R³, R⁴ and R⁵ are bonded,        wherein the monocyclic or polycyclic ring system is optionally        substituted with one or more substituents selected ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,        OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸,        C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈        cycloalkyl, C₃₋₁₈ heterocycloalkyl, and C₅₋₁₈heteroaryl, the        latter 4 groups being optionally substituted with one or more        substituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl,        and C₂₋₁₆alkenyl;    -   R⁶, R⁷, R⁸ and R⁹ are independently selected from H and        C₁₋₆alkyl;    -   n is an integer selected from 0 to 4, and        all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the compound of Formula (I), compound of Formula (II)and compound of Formula (III) are as defined above.

In an embodiment, the dehydrating agent is selected from magnesiumsulfate, sodium sulfate, aluminium phosphate, calcium oxide, cyanuricchloride, orthoformic acid, phosphorus pentoxide, sulfuric acid andmolecular sieves, and combinations thereof. In an embodiment, thedehydrating agent is selected from magnesium sulfate, sodium sulfate,aluminium phosphate, calcium oxide, cyanuric chloride, orthoformic acid,phosphorus pentoxide, and molecular sieves, and combinations thereof. Inan embodiment, the dehydrating agent is magnesium sulfate.

The Applicants have found that the alumina can be acidic alumina.Therefore, it would be appreciated by a person skilled in the art thatacid can be added to the alumina in process of the application.Therefore, in an embodiment, the application also includes a process forpreparing the compound of Formula (I) comprising reacting a compound ofFormula (II) with a compound of Formula (III) in the presence of aluminaand an acid and in a non-protic solvent to form the compound of Formula(I), wherein the compounds of Formula (I), (II) and (III) are as definedabove.

In an embodiment the acid is selected from a Lewis acid and a Bronstedacid, and a combination thereof. In an embodiment, the Lewis Acids isselected from boron trichloride, boron trifluoride, boron trifluoridediethyl etherate, iron (III) bromide, iron (III) chloride, aluminumchloride, aluminum bromide, tin (IV) chloride, titanium (IV) chloride,and titanium (IV) isopropoxide and a combination thereof. In anembodiment, the Bronsted acids is selected from hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid, acetic acid,trifluoroacetic acid, toluene sulfonic acid, trichloroacetic acid, boricacid, oleic acid, palmitic acid, and camphor sulfonic acid and acombination thereof.

In an embodiment, the forming of the compound of Formula (I) in thepresence of alumina and a further additive such as a dehydrating agentand/or an acid in a non-protic solvent are under conditions as describedabove for the forming of the compound of Formula (I) in the presence ofalumina in a non-protic solvent.

In an embodiment, the compound of Formula (I) is a compound of Formula(I-A) as defined above.

The Applicants have also shown that compound of Formula (I) can beformed by reacting the compound of Formula (II) with a compound ofFormula (III) in the presence of an aluminum alkoxide such as aluminumisopropoxide to provide a compound of Formula (I). Therefore, in anembodiment, the aluminum compound is aluminum alkoxide.

Accordingly, the application also includes a process for preparing acompound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in the presence of an aluminum alkoxide and in a non-protic solvent toform the compound of Formula (I),

-   -   wherein:    -   each R¹ is independently selected from OH, halo, CN, NO₂, COOH,        C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈cycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl, O₃₋₁₈heterocycloalkyl,        C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl,        C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,        C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈ aryl,        C₂₋₁₆alkynyleneC₆₋₁₈ aryl, C₅₋₁₈heteroaryl,        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyl, Z—C₂₋₁₆alkenyl,        Z—C₂₋₁₆alkynyl, Z—C₃₋₁₈cycloalkyl,        Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈        cycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl, Z—C₃₋₁₈        heterocycloalkyl, Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, Z—C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, Z—C₆₋₁₈ aryl, Z—C₁₋₁₆alkyleneC₆₋₁₈aryl,        Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkynyleneC₆₋₁₈aryl,        Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl,        Z—C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, and        Z—C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,    -   wherein all alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl heterocycloalkyl, aryl, and heteroaryl        groups are optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; or    -   when n is greater than 1, two R¹ groups are linked together to        form a polycyclic ring system having 8 or more atoms together        with the phenyl ring to which said groups are bonded, and in        which one or more carbon atoms in said polycyclic ring system is        optionally replaced with a heteromoiety selected from NR⁶, O and        S, wherein the polycyclic ring system is optionally substituted        with one or more substituents selected from ═O, OH, halo,        C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₂₋₁₆alkenyl,        OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,        C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,        C₂₋₁₆alkynyleneOR⁸, O₆₋₁₈aryl, C₃₋₁₈cycloalkyl,        C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heteroaryl, the latter 4 groups        being optionally substituted with one or more substituents        selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and        C₂₋₁₆alkenyl;    -   Z is selected from O, C(O), CO₂, S, SO₂, SO, and NR⁷;    -   R² is H,    -   R³ is selected from H and C₁₋₆alkyl,    -   R⁴ is selected from H, C₁₋₆alkyl, C₆₋₁₈aryl,        C₁₋₁₆alkyleneC₆₋₁₈aryl, C₅₋₁₈heteroaryl, and        C₂₋₁₆alkyleneC₅₋₁₈heteroaryl;    -   R⁵ is selected from H, C₁₋₂₆alkyl, C₂₋₂₆alkenyl, C₂₋₂₆alkynyl,        C₃₋₁₈ cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ cycloalkyl,        C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈cycloalkyl,        C₃₋₁₈ heterocycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,        C₁₋₁₆alkenyleneC₃₋₁₈ heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈        heterocycloalkyl, C₆₋₁₈aryl, C₁₋₁₆alkyleneC₆₋₁₈ aryl,        C₂₋₁₆alkenyleneC₆₋₁₈aryl, C₂₋₁₆alkynyleneC₆₋₁₈aryl,        C₅₋₁₈heteroaryl, C₂₋₁₆alkyleneC₅₋₁₈heteroaryl,        C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkynyleneC₅₋₁₈heteroaryl,        wherein all cycloalkyl, heterocycloalkyl, aryl and heteroaryl        are optionally substituted with one or more substituents        selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,        C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl,        C₁₋₁₆alkyleneOR⁹ C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹,        SO₃C₁₋₁₆alkyl, SO₃C₆₋₁₆ aryl, and SO₃C₅₋₁₈ heteroaryl        substituted with C₁₋₁₆alkyl; or any two of R², R³, R⁴ and R⁵ are        linked together to form an unsubstituted or substituted        monocyclic or polycyclic ring system having 4 or more atoms        together with the carbon atoms to which said any two of R², R³,        R⁴ and R⁵ are bonded, wherein the monocyclic or polycyclic ring        system is optionally substituted with one or more substituents        selected ═O, OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl,        OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸,        C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl,        C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the        latter 4 groups being optionally substituted with one or more        substituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl,        and C₂₋₁₆alkenyl;    -   R⁶, R⁷, R⁸ and R⁹ are independently selected from H and        C₁₋₆alkyl;    -   n is an integer selected from 0 to 4, and        all alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene,        cycloalkyl, and heterocycloalkyl groups are optionally        fluoro-substituted.

In an embodiment, the compound of Formula (I), compound of Formula (II)and compound of Formula (III) are as defined above.

In an embodiment, the forming of the compound of Formula (I) in thepresence of aluminum alkoxide in a non-protic solvent are underconditions as described above for the forming of the compound of Formula(I) in the presence of alumina in a non-protic solvent.

In an embodiment, the aluminum alkoxide is an aluminum C₁₋₁₀alkoxide. Inan embodiment, the aluminum alkoxide is an aluminum C₁₋₆alkoxide. In anembodiment, the aluminum alkoxide is selected from aluminum methoxide,aluminum ethoxide, aluminum-n-propoxide, aluminum isopropoxide,aluminum-n-butoxide, aluminum-sec-butoxide, aluminum-iso-propoxide andaluminum tert-butoxide. In an embodiment, the aluminum alkoxide isaluminum isopropoxide.

In an embodiment, it would be appreciated by a person skilled in the artthat that the aluminum alkoxide can be conjugated to any solid supportknown in the art.

In an embodiment, compound of Formula (II) and the compound of Formula(III) are both available from commercial sources or can be preparedusing methods known in the art.

In an embodiment, it would also be appreciated that the compound ofFormula (I) can be formed by reacting the compound of Formula (II) witha compound of Formula (III) in the presence of aluminum alkoxide incombination with further additives including dehydrating reagents suchas and magnesium sulfate and/or various acids as described above.

In an embodiment, it would also be appreciated that the compound ofFormula (I) can be formed by reacting the compound of Formula (II) witha compound of Formula (III) in the presence of aluminum alkoxide incombination with further additives including dehydrating reagents suchas magnesium sulfate and/or various acids as described above.

In an embodiment, the alumina (e.g., neutral, basic and acidic alumina)is available from commercial sources.

In an embodiment, the aluminum alkoxide (e.g aluminum isopropoxide) isavailable from commercial sources.

III. Compounds of the Application

The present application also includes novel compounds of Formula (I).

Accordingly, the present application includes compounds of Formula (I)selected from the compounds listed below or a salt, solvate and/orprodrug thereof:

Compound I.D Structure I-18 

I-23 

I-24 

I-27 

I-34 

I-42 

I-43 

I-45 

I-47 

I-48 

I-51 

I-52 

I-53 

I-55 

I-56 

I-58 

I-59 

I-60 

I-126

I-127

I-128

I-141

I-142

In some embodiments, the salt, solvate and/or prodrug of the compound ofFormula I is a pharmaceutically acceptable salt, solvate and/or prodrug.

In some embodiments, the pharmaceutically acceptable salt is an acidaddition salt or a base addition salt. The selection of a suitable saltmay be made by a person skilled in the art. Suitable salts include acidaddition salts that may, for example, be formed by mixing a solution ofa compound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, orbenzoic acid. Additionally, acids that are generally considered suitablefor the formation of pharmaceutically useful salts from basicpharmaceutical compounds are discussed, for example, by P. Stahl et al,Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties,Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal ofPharmaceutical Sciences 1977 66(1) 1-19; P. Gould, International J. ofPharmaceutics (1986) 33 201-217; Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; and in The OrangeBook (Food & Drug Administration, Washington, D.C. on their website).

An acid addition salt suitable for, or compatible with, the treatment ofsubjects is any non-toxic organic or inorganic acid addition salt of anybasic compound. Basic compounds that form an acid addition salt include,for example, compounds comprising an amine group. Illustrative inorganicacids which form suitable salts include hydrochloric, hydrobromic,sulfuric, nitric and phosphoric acids, as well as acidic metal saltssuch as sodium monohydrogen orthophosphate and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includemono-, di- and tricarboxylic acids. Illustrative of such organic acidsare, for example, acetic, trifluoroacetic, propionic, glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic,cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acidand other sulfonic acids such as methanesulfonic acid, ethanesulfonicacid and 2-hydroxyethanesulfonic acid. In some embodiments, exemplaryacid addition salts also include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates(“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates,propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.In some embodiments, the mono- or di-acid salts are formed and suchsalts exist in either a hydrated, solvated or substantially anhydrousform. In general, acid addition salts are more soluble in water andvarious protic organic solvents and generally demonstrate higher meltingpoints in comparison to their free base forms. The selection criteriafor the appropriate salt will be known to one skilled in the art. Othernon-pharmaceutically acceptable salts such as but not limited tooxalates may be used, for example in the isolation of compounds of theapplication for laboratory use, or for subsequent conversion to apharmaceutically acceptable acid addition salt.

A base addition salt suitable for, or compatible with, the treatment ofsubjects is any non-toxic organic or inorganic base addition salt of anyacidic compound. Acidic compounds that form a basic addition saltinclude, for example, compounds comprising a carboxylic acid group.Illustrative inorganic bases which form suitable salts include lithium,sodium, potassium, calcium, magnesium or barium hydroxide as well asammonia. Illustrative organic bases which form suitable salts includealiphatic, alicyclic or aromatic organic amines such as isopropylamine,methylamine, trimethylamine, picoline, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplaryorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine. The selectionof the appropriate salt may be useful, for example, so that an esterfunctionality, if any, elsewhere in a compound is not hydrolyzed. Theselection criteria for the appropriate salt will be known to one skilledin the art. In some embodiments, exemplary basic salts also includeammonium salts, alkali metal salts such as sodium, lithium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases (for example, organic amines) such asdicyclohexylamine, Abutyl amine, choline and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen containing groups maybe quarternized with agents such as lower alkyl halides (e.g., methyl,ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates(e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides(e.g., decyl, lauryl and stearyl chlorides, bromides and iodides),aralkyl halides (e.g., benzyl and phenethyl bromides) and others.Compounds carrying an acidic moiety can be mixed with suitablepharmaceutically acceptable salts to provide, for example, alkali metalsalts (e.g., sodium or potassium salts), alkaline earth metal salts(e.g., calcium or magnesium salts) and salts formed with suitableorganic ligands such as quaternary ammonium salts. Also, in the case ofan acid (—COOH) or alcohol group being present, pharmaceuticallyacceptable esters can be employed to modify the solubility or hydrolysischaracteristics of the compound.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the application and all acid andbase salts are considered equivalent to the free forms of thecorresponding compounds for purposes of the application. In addition,when a compound of the application contains both a basic moiety, suchas, but not limited to an aliphatic primary, secondary, tertiary orcyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole andan acidic moiety, such as, but not limited to tetrazole or carboxylicacid, zwitterions (“inner salts”) may be formed and are included withinthe terms “salt(s)” as used herein. It is understood that certaincompounds of the application may exist in zwitterionic form, having bothanionic and cationic centers within the same compound and a net neutralcharge. Such zwitterions are included within the application.

Solvates of compounds of the application include, for example, thosemade with solvents that are pharmaceutically acceptable. Examples ofsuch solvents include water (resulting solvate is called a hydrate) andethanol and the like. Suitable solvents are physiologically tolerable atthe dosage administered.

EXAMPLES

The following non-limiting examples are illustrative of the presentapplication.

Example 1 General Experimental Procedures

Alumina was purchased from Millipore Sigma (activated, acidic, BrockmannI, catalogue #199966; activated neutral, Brockmann I, catalogue #199974;activated, basic, Brockmann I, catalogue #199443). Substrates werepurchased from AKScientific and used as obtained. Solvents werepurchased from Fisher Scientific, reagent grade, and used withoutfurther purification.

¹H NMR spectra were acquired at 700 MHz with a default digitalresolution (Bruker parameter: FIDRES) of 0.15 Hz/point. Couplingconstants reported herein therefore have uncertainties of ±0.30 Hz.Chemical shifts in ¹H NMR and ¹³C NMR spectra are reported in parts permillion (ppm) with reference to residual chloroform (δ_(H) 7.26) anddeuterated chloroform (δ_(c) 77.16). Peak multiplicities are reportedusing the following abbreviations: s, singlet; d, doublet; t, triplet;q, quartet; dd, doublet of doublets; m, multiplet. Reaction progress wasmonitored by thin layer chromatography (TLC, EMD Chemicals, Inc., silicagel 60 F254). TLC plates were developed via capillary action inhexane-ethyl acetate solvent mixtures then visualized under UV lightfollowed by p-anisaldehyde stain. An automated flash chromatographysystem (Teledyne CombiFlash R_(f) 200) was used for the purification ofcompounds on silica gel (either 40-60 μM particle size).

Cannabigerol (CBG, I-1)

To a solution of geraniol (173.5 μL, 1.0 mmol) and olivetol (270.4 mg,1.5 mmol) in DCE (5 mL) was added alumina (2.0 g). The heterogenousmixture was stirred at reflux temperature for 6 hours then cooled toambient temperature and filtered through a Celite® plug. The filter cakewas rinsed with ethyl acetate (3×10 mL portions) and the filtrate wasconcentrated in vacuo to afford a yellow oil. This residue was purifiedvia chromatography using a silica gel eluted with hexane and ethylacetate. Product rich fractions were pooled and evaporated to afford I-1(162 mg, 62%) as a yellow oil. R_(f)=0.49 (ethyl acetate/hexane 30:70).¹H NMR (700 MHz, CDCl₃): δ 6.25 (2H, s), 5.27 (1H, td, J=7.1, 1.0 Hz,),5.05 (3H, m), 3.39 (2H, d, J=7.1 Hz,), 2.46 (2H, t, J=7.8 Hz,), 2.11(2H, q, J=7.4 Hz), 2.06 (2H, d, J=7.4 Hz), 1.81 (3H, s), 1.68 (3H, s),1.60 (3H, s), 1.56 (2H, q, J=7.2 Hz), 1.36-1.28 (4H, m), 0.89 (3H, t,J=6.9 Hz). DEPTQ ¹³C NMR (176 MHz, CDCl₃): δ 154.9 (C), 142.9 (C), 139.1(C), 132.2 (C), 123.9 (CH), 121.8 (CH), 110.7 (C), 108.5 (CH), 39.8(CH₂), 35.7 (CH₂), 31.6 (CH₂), 30.9 (CH₂), 26.5 (CH₂), 25.8 (CH₃), 22.7(CH₂), 22.4 (CH₂), 17.8 (CH₃), 16.3 (CH₃), 14.2 (CH₃).

Grifolin,(E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-methylbenzene-1,3-diol (I-2)

To a solution of farnesol (251 μL, 1.0 mmol) and orcinol (372 mg, 3.0mmol) in DCE (5 mL) was added acidic alumina (2.0 g). The heterogeneousmixture was stirred at reflux temperature for 7 hours then cooled toambient temperature and filtered through a Celite® plug. The filter cakewas rinsed with ethyl acetate (3×10 mL portions) and the filtrate wasconcentrated in vacuo to afford a yellow oil. This residue was purifiedvia chromatography using a silica gel eluted with hexane and ethylacetate. Product rich fractions were pooled and evaporated to afford I-2(121 mg, 37%) as a yellow oil. R_(f)=0.57 (EtOAc/Hex 25:75). ¹H NMR (700MHz, CDCl₃): δ 6.25 (2H, s), 5.48 (2H, s), 5.29 (1H, t, J=7.0 Hz), 5.12(2H, q, J=7.1 Hz), 3.42 (2H, d, J=7.1 Hz), 2.21 (3H, s), 2.10 (2H, q,J=6.9 Hz), 2.09-2.07 (4H, m), 2.01-1.99 (2H, m), 1.83 (3H, s), 1.70 (3H,s), 1.63 (3H, s), 1.61 (3H, s). DEPTQ ¹³C NMR (176 MHz, CDCl₃) δ 154.9(C), 138.9 (C), 137.5 (C), 135.7 (C), 131.4 (C), 124.5 (CH), 123.7 (CH),121.9 (CH), 110.7 (C), 109.2 (CH), 39.8 (CH₂), 39.8 (CH₂), 26.8 (CH₂),26.5 (CH₂), 25.8 (CH₃), 22.3 (CH₂), 21.1 (CH₃), 17.8 (CH₃), 16.3 (CH₃),16.1 (CH₃).

Cannabigerorcin,E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-methylbenzene-1,3-diol (I-3)

To a solution of geraniol (838 μL, 4.0 mmol) and orcinol (617 mg, 6.0mmol) in DCE was added acidic alumina (2.0 g). The heterogenous mixturewas stirred at reflux temperature for 24 hours then cooled to ambienttemperature and filtered through a Celite® plug. The filter cake wasrinsed with ethyl acetate (3×15 mL portions) and the filtrate wasconcentrated in vacuo to afford a yellow oil. This residue was purifiedvia chromatography using a silica gel eluted with hexane and ethylacetate. Product rich fractions were pooled and evaporated to afford I-3(492 mg, 47%) as a yellow oil. R_(f)=0.41 (ethyl acetate/hexane 25:75).δ ¹H NMR (700 MHz, CDCl₃) δ 6.24 (2H, s), 5.28-5.26 (1H, m), 5.07 (2H,s), 5.05 (1H, d, J=6.9 Hz), 3.39 (2H, d, J=7.1 Hz), 2.21 (3H, s), 2.10(2H, dd, J=7.3, 6.9 Hz), 2.06 (2H, dd, J=8.7, 6.3 Hz), 1.81 (3H, s),1.68 (4H, s), 1.59 (3H, s). DEPTQ ¹³C NMR (175 MHz, CDCl₃): δ 154.8 (C),139.0 (C), 137.6 (C), 132.1 (C), 123.8 (CH), 121.7 (CH), 110.5 (C),109.1 (CH), 39.7 (CH₂), 26.4 (CH₂), 25.7 (CH₃), 22.2 (CH₂), 21.1 (CH₃),17.7 (CH₃), 16.2 (CH₃).

Piperogalin,(E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-methyl-4-(3-methylbut-2-en-1-yl)benzene-1,3-diol(I-4)

To a solution of cannabigerorcin (78 mg, 0.3 mmol) and3-methylbut-2-en-1-ol (20.3 μL, 0.2 mmol) in heptanes (3.0 mL) was addedacidic alumina (300 mg). The reaction was heated to 80° C. for 14 hoursthen cooled to ambient temperature and filtered through a Celite® pad.The filter cake was rinsed with ethyl acetate (3×10 mL) and the filtratewas concentrated in vacuo to afford a yellow oil. This residue waspurified via chromatography using a silica gel eluted with hexane andethyl acetate. Product rich fractions were pooled and evaporated toafford I-4 (37.5 mg, 57%) as a yellow oil. R_(f)=0.46 (EtOAc/Hex 1:6).¹H NMR (700 MHz, CDCl₃): δ 6.27 (1H, s), 5.38 (1H, s), 5.25 (1H, t,J=7.0 Hz), 5.14 (1H, t, J=6.4 Hz), 5.06 (1H, t, J=6.4 Hz), 4.90 (1H, s),3.40 (2H, d, J=7.0 Hz), 3.29 (2H, d, J=7.0 Hz), 2.21 (3H, s,), 2.11 (2H,q, J=7.5 Hz), 2.07-2.04 (2H, m), 1.81 (3H, s), 1.80 (3H, s), 1.73 (3H,s), 1.68 (3H, s), 1.59 (3H, s). DEPTQ ¹³C NMR (176 MHz, CDCl₃): δ 153.6(C), 152.8 (C), 138.8 (C), 135.4 (C), 133.7 (C), 132.1 (C), 124.0 (CH),122.6 (CH), 122.1 (CH), 118.2 (C), 111.5 (C), 109.9 (CH), 39.8 (CH₂),26.5 (CH₂), 25.9 (CH₃), 25.8 (CH₃), 25.7 (CH₂), 22.7 (CH₂), 20.0 (CH₃),18.0 (CH₃), 17.8 (CH₃), 16.3 (CH₃).

Results and Discussion

Two syntheses of an exemplary compound of Formula (I), cannabigerol(CBG) (I-1), are reported in the literature, both proceeding viaC-alkylation of an exemplary compound of Formula (II), olivetol (II-1)with an exemplary compound of Formula (111), geraniol (III-1) (Scheme1). In 1995, Baek and co-workers treated these two substrates with borontrifluoride etherate on silica in dichloromethane to afford cannabigerolin 29% yield (Scheme 1).¹⁸ One year later, Morimoto and co-workersreported the use of p-toluenesulfonic acid in chloroform to obtaincannabigerol from the same two substrates in 40% yield,¹⁹ following asimilar procedure to that described in 1969 by Mechoulam and Yagen.²⁹(Table 1).

TABLE 1 Reported Conditions Yield Baek, 1995¹⁸ BF₃•EtO₂, SiO₂, 29%CH₂Cl₂, r.t., Morimoto, 1996 ¹⁹ TSOH, CH₃Cl, r.t., 40%

The pairing of acidic alumina with non-protic solvents like hexane or1,2-dichloroethane (DCE) as useful conditions for promoting an indolealkylation reaction was recently identified.²¹ When analogous conditionswere applied to the reaction of exemplary compound of Formula (II),olivetol (II-1), with III-1 a relatively selective and clean formationof I-1 in 34% yield (Table 2, entry 1) was surprisingly observed. Theonly other observable product was di-geranylated compound A, in 11%yield. A preliminary optimization study of this process (scheme 2) issummarized in Table 2. It was found that acidic alumina was better tobasic and neutral aluminas (entries I-3) and that (1,2-dichloroethane)DCE was a suitable solvent (entries 6-10). Under these conditions (e.g.,acidic alumina and DCE solvent) byproduct A was formed in 10% NMR yieldand easily removed using silica chromatography. Ultimately, CBG (I-1)was obtained 62% isolated yield under the following conditions (entry8): excess I-1 (1.5 equiv.) in DCE at reflux temperature (83° C.) for 6hours in the presence of acidic alumina (2 g/mmol with respect toIII-1). To the best of the Applicant's knowledge, this constitutes themost efficient synthesis of this natural product reported to date.Notably, cannabigerol (CBG, I-1) is of industrial significance as asubstrate for a bioenzymatic synthesis of tetrahydrocannabinol (THC).²²

TABLE 2 Optimization study of alumina-promoted CBG synthesis AluminaII-1 III-1 I-1 A Entry Type Amt (g) Solvent (mmol) (mmol) (%)^(a)(%)^(a) 1 Acidic 2 Hexane 1 1 34 11 2 Neutral 2 Hexane 1 1 12 2 3 Basic2 Hexane 1 1 4 1 4 Acidic 2 Hexane 1 1.5 39 13 5 Acidic 2 Hexane 1.5 153 12 6 Acidic 1 Hexane 1.5 1 22 13 7 Acidic 2 Heptanes 1.5 1 15 13 8Acidic 2 DCE 1.5 1 67 10 (62^(b)) 9 Acidic 2 CH₃CN 1.5 1 9 3 10 Acidic 2MeOH 1.5 1 0 0 11 none 0 DCE 1.5 1 0 0 ^(a)Yield determined by ¹H NMRwith dibromomethane as the internal standard. ^(b)Isolated yield afterchromatography.

Cannabigerol is structurally analogous to exemplary compound, grifolin(II-2), a natural product isolated in 1950 by Hirata from the mushroomGrifola confluens (Scheme 3).²³ Extensive bioactivity investigations ofII-2 have shown it to be a tyrosinase inhibitor,²⁴ an antioxidant,²⁵ anantihistamine agent,²⁶ an antitumor agent,²⁷⁻³⁶ an antimicrobial,²¹hypocholesterolemic,³¹ a carbonic anhydrase inhibitor,³² and aninhibitor of nitric oxide production.³³ Whether a simple one stepsynthesis of II-2 was possible using a process analogous to thecannabigerol synthesis described was investigated. Indeed, after acursory optimization of substrate ratios it was found that a refluxingmixture of exemplary compound of Formula (III), farnesol (III-2, 1.0mmol) and exemplary compound of Formula (II), orcinol (II-2, 3.0 mmol)and acidic alumina (2.0 g) in DCE offered II-2 in 37% isolated yieldafter a 7 hour reaction time (Scheme 3). This simple one step processcompares favorably with four previous synthetic preparations of thiscompound which utilized reaction sequences ranging from four to sevensteps in length (Scheme 2).³⁴⁻³⁷

Seeking to further demonstrate the utility of this alumina-promotedallylation reaction, a third natural product called piperogalin (I-4)which was isolated in 1995 from Peperomia galioides, ³⁸ and later fromPeperomia obtusifolia but had yet to be accessed via chemical synthesis(Scheme 3),³⁹ was investigated. I-4 has demonstrated antiparasiticactivity against Leishmania and Trypanosoma cruzi. ⁴% s illustrated inScheme 4, the two step sequence began with a geranylation of II-2. Inthis case, the reaction was run on a 4 mmol scale and it was opted toreduce the alumina loading to 2 g/mmol to facilitate magnetic stirringof the heterogenous reaction mixture. The reaction required 24 hours inrefluxing DCE and offered cannabigerocin (I-3) in 47% isolated yield.Next, prenylation of I-3 was initially low yielding in DCE and requiredsome effort to optimize solvent, reaction temperature, and substrateratios. Ultimately, I-4 was obtained in 57% yield when the reaction wasrun in heptanes, with 1.5 equiv. of prenol and 1.5 g/mmol of aluminarelative to I-3, and the temperature maintained at 80° C. for 14 hours.Considerably reduced yields were observed when the reaction wasperformed at 98° C., the reflux temperature of heptanes, as I-4 appearedto be prone to further reactions resulting in a complex mixture ofunidentified byproducts evident in the crude ¹H NMR spectrum. Overall,this regioselective geranylation and prenylation sequence offered thefirst total synthesis of I-4 in 27% overall yield in two steps fromII-2.

Accordingly, the utility of an exemplary regioselective alumina-promotedallylation reaction of resorcinols was investigated which has enabledefficient syntheses of the natural products cannabigerol (CBG, I-1),grifolin (I-2), cannabigerorcin (I-3) and piperogalin (I-4).

Example 2

The allylation of model compound of Formula (II) (phenol II-3, wherein nis 1 and R¹ is H) with a compound of Formula (III)((E)-3-phenylprop-2-en-1-ol wherein R² to R⁴ are H and R⁵ is phenyl(III-3, cinnamyl alcohol)) using the alumina (acidic) in DCE accordingto the process described herein in comparison with other reactionconditions known in the art was investigated (Scheme 5). A summary ofthe results of the investigation is provided in Table 3.

Conditions: II-3 (0.75 mmol), III-3 (0.5 mmol), acidic alumina (1 g) andsolvent (5 mL) in a 40 mL reaction vial, charged with a stir bar, themixture was heated at refluxing temperature for 24 h. Then was filteredthrough a pad of Cellite®. The residue was washed by EtOAc 3 times,solvent was removed in vacuo.

TABLE 3 Reaction Conditions I-5 B C D Alumina (acidic) DCE, 79%  0% 10% 0% reflux, 24 hr BF₃ •OEt₂ (1.0 equiv), 10% 42% 0% 9% DCE, r.t., 15 minZnBr₂ (1.0 equiv) DCE,  7% 34% 0% 6% r.t., 2 hr TsOH (1.0 equiv) DCE,21% 30% 0% 8% r.t., 24 hr FeCl₃ (1.0 equiv) DCE,  4% 35% 0% Trace r.t.,30 min Sc(OTf)₃ (1.0 equiv) Trace 22% 0% Trace DCE, r.t., 30 min AgOTf(1.0 equiv) DCE, 21% 36% 0% 9% r.t., 1 hr ZrCl₄ (1.0 equiv) DCE,  0% 10%0% 0% r.t., 30 min TFA (1.0 equiv) DCE,  9% 35% 0% 5% r.t., 3 days

Discussion

The alumina-mediated allylation yielded primarily I-5 and theo,o-disubstituted phenol compound C (Scheme 5). In contrast, the 8 otherLewis or Bronsted acids evaluated all resulted in the para-allylationproduct compound B as the major product of the reaction. In contrast tothe other acids, formation of para-substitution products, compounds Band D, was not observed with alumina. Instead, the only productsobserved via ¹H NMR spectrum of the crude reaction mixtures wereortho-substituted I-5, in 79% yield, and ortho-disubstituted compound C,in 10% yield. This reaction was not inhibited by the radical scavengerBHT, ruling out a potential radical process.

Example 3

An study of an exemplary process of the application with model compoundof Formula (II) wherein n is 1 and R¹ is H (phenol (II-3), with acompound of Formula (III) wherein R² to R⁴ are H and R⁵ is phenyl((E)-3-phenylprop-2-en-1-ol, III-3, cinnamyl alcohol) was conducted(Scheme 6). A summary of the results of the study is provided in Table4.

TABLE 4 Deviation from acid (%) Yield (%) Yield (%) Yield Entry aluminaand DCE I-5^(a) B^(a) C^(a) 1 None 79 (73^(b)) 10 (9^(b)) 0 2 Neutralalumina instead of 20 1 0 Acidic alumina 3 Basic alumina instead of 4810 0 Acidic alumina 4 Hexane instead of DCE 55 8 0 5 Toluene instead ofDCE 48 10 0 6 DCM instead of DCE 0 0 0 7 DCM at 84° C. instead ofDCE^(c) 68 8 0 8 Et₂O instead of DCE 0 0 0 9 EtOAc instead of DCE 0 0 010 CH₃CN instead of DCE 0 0 0 11 EtOH instead of DCE 0 0 0 12 II-3:III-3(2.0:1.0) 68 8 0 13 II-3:III-3 (1.0:1.0) 43 13 0 14 II-3:III-3 (1.0:1.5)43 21 0 15 II-3:III-3 (1.0:2.0) 42 20 0 16 Acidic alumina (0.5 g) 55 3 017 Acidic alumina (0 g) 0 0 0 ^(a)Yields were determined by ¹H NMRanalysis of the crude reaction mixture with an internal standard CH₂Br₂;^(b)Isolated yield; ^(c)Reaction in pressure tube.

Conditions for reaction: II-2 (0.75 mmol), III-3 (0.5 mmol), acidicalumina (1 g), dichloroethane (5 mL), reflux, 24 h; then filtrationthrough pad of Celite®, rinsed with EtOAc (×3); solvent removed invacuo. ^(a)Yields were determined by ¹H NMR analysis of the crudereaction mixture using CH₂Br₂ as an internal standard;^(b)Isolatedyield;^(c)Reaction was performed in a pressure tube.

Consistent yields of I-5 were obtained with six acidic aluminaspurchased from different vendors (see Example 4). Spent alumina iseasily recovered from this reaction by filtration. When the spentalumina was dried by heating at 90° C. under a strong vacuum for fivehours, it was found that it could be reused in repeated reactions with aconsistently high yield of I-5 obtained over, for example, five cycles.

Example 4

The effect of various commercially available acidic alumina on anexemplary process of the application (Scheme 7) was investigated. Theresults are summarized in Table 5.

Conditions: II-3 (1.5 mmol), III-3 (1.0 mmol), acidic alumina (2 g) andDCE (10 mL) in a 40 mL reaction vial, charged with a stir bar, themixture was heated at refluxing temperature for 24 h. Then was filteredthrough a pad of Cellite. The residue was washed by EtOAc 3 times,solvent was removed in vacuo.

TABLE 5 Alumina (%) Yield (%) Yield (%) Yield Entry (acidic) I-5 B^(a)C^(a) 1 Millipore 73 13 0 2 Acros 74 11 0 3 MP 75 13 0 4 Honeywell 72 110 5 Alfa Aesar 76 12 0 6 Fisher 72 11 0 ^(a)Yields were determined by ¹HNMR analysis of the crude reaction mixture with an internal standardCH₂Br₂

Discussion

The 6 aluminas obtained from different manufacturers all resulted incomparable yields of I-5 and compound B with no observablepara-substitution product (compound C) in any of the reactions.

Example 5: Preparation of Exemplary Compounds of Formula (I) Using theProcess of the Application

To probe the synthetic utility of this reaction, a range of stericallyand electronically diverse phenols and allylic alcohols were subjectedto the conditions as described in Example 4. A steric hindrance effectwas observed for ortho substituted phenols (I-19, I-39 and I-16). Assteric bulk increased, reaction yields lowered and reaction rates wereslower. Substrates I-19 and I-39 showed incomplete consumption ofcinnamyl alcohol after two days. Additionally, meta substituted phenols(I-14 to I-17, I-44, I-26, I-51 and I-13) were preferentially allylatedat the less hindered position. Exceptions to this included resorcinol(I-15) and 2-naphthol (I-11 and I-53). Electron-poor phenols had reducedselectivity and lower yields (I-55, I-56, I-42, I-43). Additionally,indoles I-24 and I-24 demonstrated poor regioselectivity. Notably, the1,4-quinone corresponding to the 1,4-dihydroxyl benzene (I-13) whichpresumably resulted from air-oxidation was isolated. Evaluation ofallylic alcohols demonstrated that this reaction is effective forelectron-rich, electron-poor, and aliphatic alcohols (I-27, I-28, I-29,I-9, I-47, I-46, I-30, I-31, I-41, I-48, I-32, I-33, I-38, I-37). Thenatural hormones estrone, estradiol and the birth control drugethinylestradiol underwent cinnamylation at less hinderedortho-positions relative to phenolic hydroxyl group (I-58 to I-60).These substrates highlight the potential applicability of thisallylation reaction to late-stage functionalization of phenolic naturalproducts and pharmaceuticals.

Table 6 is a summary of exemplary compound of Formula (I) prepared usingthe process of the application and the corresponding yields of thereaction.

TABLE 6

Synthesis of Exemplary Compounds of Formula (I) from Table 6 Synthesisof I-5

General Procedure: To a 40 mL reaction vial containing a magnetic stirwere added cinnamyl alcohol (134.2 mg, 1.0 mmol), 1,2-dichloroethane (10mL), acidic aluminum oxide (2.0 g), and phenol (141.2 mg, 1.5 mmol). Thesuspension was stirred and heated at reflux temperature for 24 hours atwhich point TLC analysis indicated complete consumption of the cinnamylalcohol substrate. The reaction mixture was cooled and filtered througha pad of Celite®. The solids were washed with EtOAc (3×30 mL) and thefiltrates combined and concentrated in vacuo. Unless otherwisespecified, the crude residue was purified via flash columnchromatography on silica gel using gradient elution with hexane andethyl acetate. Compound I-5 was isolated as a white solid in 9% yield(29.3 mg, 0.09 mmol) and Compound MLAP-1909 was isolated as a colorlessoil in 73% yield (153.8 mg, 0.73 mmol). R_(f)=0.63 (Hexane:EtOAc=7:3);¹H NMR (700 MHz, Chloroform-d) δ 7.36 (d, J=7.6 Hz, 2H), 7.30 (t, J=7.6Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.16 (t, J=7.7Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.52 (d, J=15.9Hz, 1H), 6.40 (dt, J=15.9, 6.6 Hz, 1H), 4.90 (s, 1H), 3.58 (d, J=6.4 Hz,2H); ¹³C NMR (176 MHz, Chloroform-d) δ 154.15, 137.22, 131.67, 130.62,128.67, 128.07, 128.04, 127.47, 126.34, 125.79, 121.17, 115.91, 34.25;HRMS: calculated for C15H13O (M-H)⁻ 209.0966; found 209.0964.

Synthesis of I-6

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), p-cresol (81.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 11 hours indicated completeconsumption of cinnamyl alcohol. Compound I-6 was isolated as acolorless oil (87.2 mg, 0.39 mmol, 78% yield); R_(f)=0.68(Hexane:EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.37 (d, J=7.3 Hz,2H), 7.31 (t, J=7.7 Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 6.99 (s, 1H), 6.95(d, J=7.9 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.52 (d, J=15.9 Hz, 1H), 6.40(dt, J=15.7, 6.6 Hz, 1H), 4.80 (s, 1H), 3.55 (d, J=6.6 Hz, 2H), 2.29 (s,3H); ¹³C NMR (176 MHz, Chloroform-d) δ 151.84, 137.28, 131.50, 131.12,130.34, 128.65, 128.39, 128.21, 127.42, 126.33, 125.53, 115.74, 34.24,20.63; HRMS: calculated for C16H15O (M-H)⁻ 223.1123; found 223.1124.

Synthesis of I-7

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), p-methoxylphenol (93.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 23 hours indicated completeconsumption of cinnamyl alcohol. Compound I-7 was isolated as acolorless oil (85.1 mg, 0.354 mmol, 71% yield); R_(f)=0.55(Hexane:EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.37-7.34 (m, 2H),7.29 (t, J=7.6 Hz, 2H), 7.23-7.20 (m, 1H), 6.78-6.73 (m, 2H), 6.69 (dd,J=8.7, 3.1 Hz, 1H), 6.50 (dt, J=16.0, 1.6 Hz, 1H), 6.37 (dt, J=15.9, 6.6Hz, 1H), 4.57 (s, 1H), 3.76 (s, 3H), 3.54 (dd, J=6.6, 1.7 Hz, 2H); ¹³CNMR (176 MHz, Chloroform-d) δ 153.99, 148.06, 137.21, 131.72, 128.65,127.84, 127.43, 126.99, 126.34, 116.61, 116.13, 112.74, 55.88, 34.48;HRMS: calculated for C16H15O2 (M-H)⁻ 239.1072; found 239.1084.

Synthesis of I-8

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 4-chlorophenol (96.4 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-8 was isolated as acolorless oil (85.1 mg, 0.354 mmol, 71% yield); R_(f)=0.57(Hexane:EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.39-7.34 (m, 2H),7.31 (t, J=7.7 Hz, 2H), 7.23 (td, J=7.1, 1.3 Hz, 1H), 7.15 (d, J=2.5 Hz,1H), 7.10 (dd, J=8.5, 2.6 Hz, 1H), 6.75 (dd, J=10.5, 8.7 Hz, 1H), 6.51(dt, J=15.9, 1.7 Hz, 1H), 6.34 (dt, J=15.8, 6.7 Hz, 1H), 5.11 (s, 1H),3.53 (dd, J=6.7, 1.6 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 152.71,137.01, 132.21, 130.22, 129.64, 128.71, 127.76, 127.70, 127.63, 127.05,126.37, 125.73, 117.06, 116.79, 33.95; HRMS: calculated for 015H12010(M-H)⁻ 243.0577; found 243.0564.

Synthesis of I-9

The general procedure was used with 4-nitrocinnamyl alcohol (89.6 mg,0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of 4-nitrocinnamyl. Com I-9 was isolated as a a yellowcrystal solid (71.3 mg, 0.279 mmol, 56% yield); R_(f)=0.45(Hexane:EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d)) δ 8.14 (d, J=8.8 Hz,2H), 7.46 (d, J=8.8 Hz, 2H), 7.16 (ddd, J=9.3, 7.4, 1.6 Hz, 2H),6.94-6.91 (m, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.61 (dt, J=15.9, 6.6 Hz,1H), 6.50 (dd, J=15.9, 1.7 Hz, 1H), 4.80 (s, 1H), 3.61 (dd, J=6.6, 1.6Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 153.73, 146.77, 144.05,133.80, 130.74, 129.28, 128.24, 126.75, 125.25, 124.11, 121.34, 115.73,34.04; HRMS: calculated for C15H12NO3 (M-H)⁻ 254.0817; found 254.0808.

Synthesis of I-10

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 1-naphthol (108.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-10 was isolated as a whitesolid (107.0 mg, 0.411 mmol, 82% yield); R_(f)=0.63 (Hexane:EtOAc=7:3);¹H NMR (700 MHz, Chloroform-d) δ 8.16 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.3Hz, 1H), 7.50-7.43 (m, 3H), 7.36 (d, J=7.5 Hz, 2H), 7.32-7.27 (m, 3H),7.23 (t, J=7.3 Hz, 1H), 6.60 (d, J=15.9 Hz, 1H), 6.45 (dt, J=15.9, 6.4Hz, 1H), 5.52 (s, 1H), 3.74 (d, J=5.4 Hz, 2H); ¹³C NMR (176 MHz,Chloroform-d) δ 149.56, 136.69, 133.80, 131.99, 128.61, 128.44, 127.61,127.46, 126.29, 125.84, 125.38, 124.81, 121.27, 120.48, 118.18, 34.78;HRMS: calculated for C19H15O (M-H)⁻ 259.1123; found 259.1112.

Synthesis of I-11

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 2-naphthol (108.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-11 was isolated as a whitesolid (120.5 mg, 0.463 mmol, 93% yield); R_(f)=0.49 (Hexane:EtOAc=7:3);¹H NMR (700 MHz, Chloroform-d)) δ 7.97 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.1Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.51-7.48 (m, 1H), 7.36 (t, J=7.5 Hz,1H), 7.30 (d, J=7.3 Hz, 2H), 7.27-7.23 (m, 2H), 7.17 (t, J=7.3 Hz, 1H),7.12 (d, J=8.8 Hz, 1H), 6.44 (d, J=3.4 Hz, 2H), 5.02 (s, 1H), 3.99 (d,J=3.3 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 151.31, 137.31, 133.42,131.10, 129.64, 128.76, 128.59, 128.57, 127.70, 127.32, 126.78, 126.28,123.40, 123.22, 118.09, 117.22, 28.62; HRMS: calculated for C19H15O(M-H)⁻ 259.1123; found 259.1113.

Synthesis of I-12

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 3,5-dimethylphenol (91.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-12 was isolated asa white solid (96.1 mg, 0.403 mmol, 81% yield); R_(f)=0.60(Hexane:EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d)) δ 7.32 (d, J=7.1 Hz,2H), 7.28-7.25 (m, 2H), 7.20-7.16 (m, 1H), 6.63 (s, 1H), 6.52 (s, 1H),6.40-6.36 (m, 1H), 6.32 (dt, J=15.8, 5.9 Hz, 1H), 4.70 (s, 1H), 3.55(dd, J=5.9, 1.5 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H); ¹³C NMR (176 MHz,Chloroform-d) δ 153.87, 137.98, 137.35, 137.02, 130.34, 128.45, 127.65,127.08, 126.12, 123.79, 120.94, 114.09, 29.53, 20.97, 19.63; HRMS:calculated for C17H17O (M-H)⁻ 237.1279; found 237.1289.

Synthesis of I-13

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 3,4-dimethylphenol (91.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-13 was isolated asa white crystal solid (121.0 mg, 0.427 mmol, 85% yield); R_(f)=0.61(Hexane:EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.38 (d, J=7.6 Hz,2H), 7.31 (t, J=7.7 Hz, 2H), 7.23 (t, J=7.3 Hz, 1H), 6.94 (s, 1H), 6.66(s, 1H), 6.53 (d, J=15.9 Hz, 1H), 6.40 (dt, J=15.9, 6.6 Hz, 1H), 4.70(s, 1H), 3.53 (d, J=6.4 Hz, 2H), 2.23 (s, 3H), 2.21 (s, 3H); ¹³C NMR(176 MHz, Chloroform-d) δ 151.97, 137.31, 136.27, 131.63, 131.33,128.92, 128.65, 128.49, 127.39, 126.34, 122.66, 117.28, 33.91, 19.58,18.86; HRMS: calculated for C17H17O (M-H)⁻ 237.1279; found 237.1280.

Synthesis of I-14

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 3-methylphenol (81.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-14 was isolated as a whitesolid (96.1 mg, 0.403 mmol, 86% Yield); R_(f)=0.55 (Hexane/EtOAc=7:3);¹H NMR (700 MHz, Chloroform-d) δ 7.35 (d, J=7.5 Hz, 2H), 7.29 (t, J=7.6Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.6Hz, 1H), 6.65 (s, 1H), 6.50 (d, J=15.9 Hz, 1H), 6.38 (dt, J=15.7, 6.6Hz, 1H), 4.82 (s, 1H), 3.53 (d, J=6.4 Hz, 2H), 2.30 (s, 3H); ¹³C NMR(176 MHz, Chloroform-d) 153.87, 138.01, 137.14, 131.35, 130.28, 128.53,128.20, 127.29, 126.20, 126.12, 122.46, 121.74, 116.51, 33.81, 21.03;HRMS: calculated for C16H15O (M-H)⁻ 223.1123; found 223.1115.

Synthesis of I-15

The general procedure was used with cinnamyl alcohol (268.4 mg, 2.0mmol), 3-hydroxyphenol (330.3 mg3.0 mmol), acidic alumina (4 g), and1,2-dichloroethane (520 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-15 was isolated as a whitesolid (238.4 mg, 1.054 mmol, 53% Yield); R_(f)=0.58 (Hexane/EtOAc=6:4);¹H NMR (700 MHz, Chloroform-d) δ 7.34 (dd, J=8.1, 1.4 Hz, 2H), 7.28 (t,J=7.7 Hz, 2H), 7.21-7.18 (m, 1H), 6.99 (t, J=8.1 Hz, 1H), 6.52 (dt,J=15.8, 1.8 Hz, 1H), 6.44 (d, J=8.1 Hz, 2H), 6.37 (dt, J=15.9, 6.4 Hz,1H), 4.90 (d, J=1.2 Hz, 2H), 3.63 (dd, J=6.3, 1.7 Hz, 2H); ¹³C NMR (176MHz, Chloroform-d) δ 155.29, 137.26, 131.02, 128.59, 127.75, 127.70,127.34, 126.32, 112.54, 108.33, 31.08, 26.80; HRMS: calculated forC15H13O2 (M-H)⁻ 225.0916; found 225.0923.

Synthesis of I-16

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 2-chlorophenol (96.4 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-16 was isolated as a yellowoil (113.6 mg, 0.464 mmol, 86% yield); R_(f)=0.62 (Hexane/EtOAc=7:3); ¹HNMR (700 MHz, Chloroform-d) δ 7.36 (d, J=7.6 Hz, 2H), 7.33-7.28 (m, 3H),7.24 (dd, J=8.2, 2.5 Hz, 2H), 6.70 (d, J=8.5 Hz, 1H), 6.51 (d, J=15.8Hz, 1H), 6.34 (dt, J=15.9, 6.7 Hz, 1H), 4.99 (s, 1H), 3.53 (d, J=6.7 Hz,2H); ¹³C NMR (176 MHz, Chloroform-d) δ 153.24, 136.97, 133.11, 132.27,130.71, 128.72, 128.23, 127.66, 126.98, 126.38, 117.60, 113.09, 33.96;HRMS: calculated for 015H12010 (M-H)⁻ 243.0577; found 243.0565.

Synthesis of I-17

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 3-chlorophenol (96.4 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-17 was isolated as a whitesolid (78.4 mg, 0.32 mmol, 64% yield); R_(f)=0.74 (Hexane/EtOAc=7:3); ¹HNMR (700 MHz, Chloroform-d) δ 7.37 (d, J=7.6 Hz, 2H), 7.30 (t, J=7.6 Hz,2H), 7.24-7.19 (m, 2H), 7.11 (d, J=7.5 Hz, 1H), 6.83 (t, J=7.8 Hz, 1H),6.48 (d, J=15.9 Hz, 1H), 6.39 (dt, J=15.7, 6.8 Hz, 1H), 5.67 (s, 1H),3.60 (d, J=6.7 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 149.41,137.54, 131.48, 129.06, 128.63, 128.12, 127.84, 127.28, 127.07, 126.27,121.03, 120.06, 33.88; HRMS: calculated for C15H12ClO (M-H)⁻ 243.0577;found 243.0571.

Synthesis of I-18

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 2,3-dimethylphenol (91.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-18 was isolated asa colorless oil (97.9 mg, 0.41 mmol, 82% yield); R_(f)=0.69(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.37 (d, J=7.5 Hz,2H), 7.31 (t, J=7.6 Hz, 2H), 7.25-7.21 (m, 1H), 6.93 (d, J=7.6 Hz, 1H),6.76 (d, J=7.6 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 6.39 (dt, J=16.0, 6.6Hz, 1H), 5.00 (d, J=1.1 Hz, 1H), 3.56 (dd, J=6.7, 1.6 Hz, 2H), 2.29 (s,3H), 2.19 (s, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ 152.39, 136.97,136.60, 131.63, 128.57, 128.18, 127.43, 127.04, 126.27, 122.95, 122.34,122.06, 34.83, 20.10, 11.68; HRMS: calculated for C17H17O (M-H)⁻237.1279; found 237.1231.

Synthesis of I-19

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 2-methylphenol (81.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 48 hours indicated cinnamylalcohol was still existed. Compound I-19 was isolated as a colorless oil(25.8 mg, 0115 mmol, 23% yield); R_(f)=0.74 (Hexane/EtOAc=7:3); ¹H NMR(700 MHz, Chloroform-d) δ 7.36 (d, J=7.6 Hz, 2H), 7.30 (t, J=7.6 Hz,2H), 7.22 (t, J=7.3 Hz, 1H), 7.04 (dd, J=12.6, 7.5 Hz, 2H), 6.83 (t,J=7.5 Hz, 1H), 6.54 (d, J=15.9 Hz, 1H), 6.40 (dt, J=15.9, 6.7 Hz, 1H),4.95 (s, 1H), 3.58 (d, J=6.4 Hz, 2H), 2.26 (s, 3H); ¹³C NMR (176 MHz,Chloroform-d) δ 152.67, 137.13, 131.76, 129.53, 128.68, 128.24, 128.16,127.52, 126.36, 125.08, 124.20, 120.61, 34.72, 16.01; HRMS: calculatedfor C16H15O (M-H)⁻ 223.1123; found 223.1132.

Synthesis of I-20

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 2,4-dimethylphenol (91.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-20 was isolated asa colorless oil (100.2 mg, 0.42 mmol, 84% yield); R_(f)=0.73(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.37 (d, J=7.3 Hz,2H), 7.31 (t, J=7.7 Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 6.87 (s, 1H), 6.84(s, 1H), 6.54 (d, J=15.9 Hz, 1H), 6.39 (dt, J=15.9, 6.7 Hz, 1H), 4.77(s, 1H), 3.54 (d, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.23 (s, 3H); ¹³C NMR(176 MHz, Chloroform-d) δ 150.34, 137.18, 131.60, 130.08, 129.74,128.67, 128.66, 128.31, 127.48, 126.36, 124.91, 124.00, 34.71, 20.60,15.97; HRMS: calculated for C17H17O (M-H)⁻ 237.1279; found 237.1286.

Synthesis of I-21

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 4-bromophenol (129.8 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 12 hours indicated completeconsumption of cinnamyl alcohol. Compound I-21 was isolated as a yellowoil (121.2 mg, 0.42 mmol, 84% yield); R_(f)=0.56 (Hexane/EtOAc=7:3); ¹HNMR (700 MHz, Chloroform-d) δ 7.36 (d, J=7.6 Hz, 2H), 7.33-7.28 (m, 3H),7.24 (dd, J=8.2, 2.5 Hz, 2H), 6.70 (d, J=8.5 Hz, 1H), 6.51 (d, J=15.8Hz, 1H), 6.34 (dt, J=15.9, 6.7 Hz, 1H), 4.99 (s, 1H), 3.53 (d, J=6.7 Hz,2H); ¹³C NMR (176 MHz, Chloroform-d) δ 153.24, 136.97, 133.11, 132.27,130.71, 128.72, 128.23, 127.66, 126.98, 126.38, 117.60, 113.09, 33.96;HRMS: calculated for C15H12BrO (M-H)⁻ 287.0072; found 287.0078.

Synthesis of I-22

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), trimethylhydroquinone (114.1 mg, 0.75 mmol), acidic alumina (1g), and 1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-22 was isolated asa yellow oil (74.4 mg, 0.277 mmol, 55% yield); R_(f)=0.76(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.32-7.30 (m, 2H),7.29-7.26 (m, 3H), 7.21-7.17 (m, 1H), 6.42 (dd, J=15.8, 1.7 Hz, 1H),6.13 (dt, J=15.8, 6.8 Hz, 1H), 3.41 (dd, J=6.8, 1.5 Hz, 2H), 2.09 (s,3H), 2.03 (d, J=2.1 Hz, 6H); ¹³C NMR (176 MHz, Chloroform-d) δ 187.87,186.93, 141.56, 141.25, 140.76, 140.59, 137.25, 131.85, 128.64, 127.46,126.24, 125.40, 30.00, 12.56, 12.54, 12.37;

Synthesis of I-23

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 4-hydroxyindole (99.9 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 5 hours indicated completeconsumption of cinnamyl alcohol. Compound I-23 was isolated as a whitecrystal solid (108.1 mg, 0.277 mmol, 55% yield); R_(f)=0.73(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.35(d, J=7.8 Hz, 2H), 7.29 (t, J=7.6 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 7.13(d, J=2.4 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.58(s, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.45 (dt, J=15.9, 6.5 Hz, 1H), 5.20(s, 1H), 3.68 (d, J=6.3 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ147.04, 137.38, 136.87, 130.94, 129.34, 128.63, 127.31, 126.33, 125.11,123.43, 118.31, 114.04, 104.11, 98.76, 34.01; HRMS: calculated forC15H12BrO (M-H)⁻ 248.1075; found 248.1081.

Synthesis of I-24

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 5-hydrooxyindole (99.9 mg, 0.75 mmol), acidic aluminum oxide (1g), and dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-24 was isolated asa colorless oil (42.5 mg, 0.170 mmol, 34% yield); R_(f)=0.65(DCM/MeOH=98:2); ¹H NMR (700 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.33 (d,J=7.6 Hz, 2H), 7.28-7.24 (m, 2H), 7.18 (dt, J=12.0, 3.2 Hz, 3H), 6.80(d, J=8.6 Hz, 1H), 6.57-6.52 (m, 2H), 6.45 (dt, J=15.9, 6.3 Hz, 1H),4.69 (s, 1H), 3.84 (dd, J=6.3, 1.2 Hz, 2H); ¹³C NMR (176 MHz,Chloroform-d) δ 147.52, 137.40, 131.24, 130.94, 128.75, 128.58, 128.19,127.27, 126.32, 124.98, 115.28, 112.82, 110.01, 100.99, 31.01;

Synthesis of I-25

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 5-hydroxyindole (99.9 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-25 was isolated as a whitesolid (40.4 mg, 0.162 mmol, 32% yield); R_(f)=0.75 (Hexane/EtOAc=7:3);¹H NMR (700 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.36 (d, J=7.3 Hz, 2H),7.30 (t, J=7.7 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.19 (s, 1H), 7.14 (t,J=2.8 Hz, 1H), 7.07 (s, 1H), 6.54-6.42 (m, 3H), 4.66 (d, J=3.0 Hz, 1H),3.67 (d, J=6.0 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 148.42,137.43, 131.54, 131.29, 128.91, 128.65, 127.34, 127.31, 126.31, 124.76,122.50, 112.03, 105.80, 101.98, 34.77; HRMS: calculated for C15H12BrO(M-H)⁻ 248.1075; found 248.1069.

Synthesis of I-26

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 3-methoxyphenol (93.1 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 11 hours indicated completeconsumption of cinnamyl alcohol. Compound I-26 was isolated as acolorless oil (108.9 mg, 0.454 mmol, 91% yield); R_(f)=0.52(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.36 (d, J=7.5 Hz,2H), 7.30 (t, J=7.6 Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 7.06 (d, J=8.2 Hz,1H), 6.52-6.43 (m, 3H), 6.38 (dt, J=15.9, 6.5 Hz, 1H), 5.23 (s, 1H),3.78 (s, 3H), 3.51 (d, J=6.4 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ159.74, 155.13, 137.23, 131.37, 131.01, 128.65, 128.50, 127.42, 126.32,117.90, 106.40, 102.19, 55.48, 33.63; HRMS: calculated for 016H1502(M-H)⁻ 239.1072; found 239.1067.

Synthesis of I-27

The general procedure was used with (E)-3-(4-fluorophenyl)prop-2-en-1-ol(76.1 mg, 0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 72 hours indicatedcomplete consumption of (E)-3-(4-fluorophenyl)prop-2-en-1-ol. CompoundI-27 was isolated as a colorless oil (87.7 mg, 38.4 mmol, 77% yield);R_(f)=0.52 (Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ7.34-7.30 (m, 2H), 7.20-7.14 (m, 2H), 6.99 (t, J=8.7 Hz, 2H), 6.92 (t,J=7.5 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.46 (d, J=15.9 Hz, 1H), 6.31(dt, J=15.7, 6.6 Hz, 1H), 5.00-4.92 (m, 2H), 3.57 (d, J=6.4 Hz, 2H); ¹³CNMR (176 MHz, Chloroform-d) δ 162.96, 161.56, 154.02, 133.45, 130.61,130.33, 128.06, 127.87, 127.79, 127.75, 125.80, 121.19, 115.85, 115.57,115.45, 34.06; HRMS: calculated for C15H12FO (M-H)⁻ 227.0872; found227.0883.

Synthesis of I-28

The general procedure was used with (E)-3-(4-chlorophenyl)prop-2-en-1-ol(84.3 mg, 0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 24 hours indicatedcomplete consumption of (E)-3-(4-chlorophenyl)prop-2-en-1-ol. CompoundI-28 was isolated as a white crystal solid (98.1 mg, 0.40 mmol, 80%yield); R_(f)=0.46 (Hexane/EtOAc=8:2); ¹H NMR (700 MHz, Chloroform-d) δ7.14-7.10 (m, 4H), 7.04-6.99 (m, 2H), 6.79-6.76 (m, 1H), 6.67 (d, J=7.9Hz, 1H), 6.29 (d, J=15.9 Hz, 1H), 6.23 (dt, J=15.9, 6.4 Hz, 1H), 4.82(s, 1H), 3.42 (d, J=6.3 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ153.95, 135.82, 132.93, 130.63, 130.22, 128.92, 128.77, 128.08, 127.50,125.70, 121.20, 115.81, 34.02; HRMS: calculated for C15H12ClO (M-H)−243.0577; found 243.0578.

Synthesis of I-29

The general procedure was used with (E)-3-(4-bromophenyl)prop-2-en-1-ol(106.6 mg, 0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 72 hours indicatedcomplete consumption of (E) (4-bromophenyl)prop-2-en-1-ol. Compound I-29was isolated as a white solid (111.4 mg, 0.385 mmol, 77% yield);R_(f)=0.44 (Hexane/EtOAc=8:2); ¹H NMR (700 MHz, Chloroform-d) 7.42-7.39(m, 2H), 7.23-7.19 (m, 2H), 7.17-7.13 (m, 2H), 6.91 (td, J=7.5, 1.2 Hz,1H), 6.81 (dd, J=7.9, 1.3 Hz, 1H), 6.45-6.34 (m, 2H), 4.90 (s, 1H), 3.55(d, J=5.3 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 153.84, 136.15,131.60, 130.51, 130.15, 128.95, 127.97, 127.72, 125.52, 121.08, 120.95,115.69, 33.93; HRMS: calculated for C15H12BrO (M-H)⁻ 287.0072; found287.0085.

Synthesis of I-30

The general procedure was used with(E)-3-(4-methoxyphenyl)prop-2-en-1-ol (82.1 mg, 0.5 mmol), phenol (70.6mg, 0.75 mmol), acidic alumina (1 g), and 1,2-dichloroethane (5 mL). TLCanalysis at 5 hours indicated complete consumption of(E)-3-(4-methoxyphenyl)prop-2-en-1-ol. Compound I-30 was isolated as awhite solid (40.6 mg, 0.169 mmol, 34% yield); R_(f)=0.62(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.30 (d, J=8.7 Hz,2H), 7.18 (d, J=7.5 Hz, 1H), 7.15 (td, J=7.8, 1.5 Hz, 1H), 6.91 (td,J=7.5, 1.0 Hz, 1H), 6.86-6.82 (m, 4H), 6.47 (d, J=15.9 Hz, 1H), 6.25(dt, J=15.9, 6.7 Hz, 1H), 5.05 (s, 1H), 3.81 (s, 3H), 3.56 (d, J=6.7 Hz,2H); ¹³C NMR (176 MHz, Chloroform-d) δ 159.15, 154.26, 131.13, 130.57,130.02, 128.02, 127.48, 125.97, 125.76, 121.08, 115.92, 114.09, 55.43,34.31; HRMS: calculated for C16H15O2 (M-H)⁻ 239.1072; found 239.1079.

Synthesis of I-31

The general procedure was used with (E)-3-(4-methylphenyl)prop-2-en-1-ol(74.1 mg, 0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g),and 1,2-dichloroethane (5 mL). TLC analysis at 48 hours indicatedcomplete consumption of (E)-3-(4-methylphenyl)prop-2-en-1-ol. CompoundI-31 was isolated as a colorless oil (93.5 mg, 0.417 mmol, 83% yield);R_(f)=0.48 (Hexane/EtOAc=8:2); ¹H NMR (700 MHz, Chloroform-d) δ7.28-7.24 (m, 2H), 7.19-7.13 (m, 2H), 7.13-7.09 (m, 2H), 6.91 (tt,J=7.5, 1.5 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.49 (dd, J=15.9, 1.8 Hz,1H), 6.34 (dtd, J=15.5, 6.7, 1.7 Hz, 1H), 5.02-4.88 (m, 1H), 3.57 (d,J=6.6 Hz, 2H), 2.33 (s, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ 154.23,137.28, 134.39, 131.61, 130.59, 129.37, 128.04, 126.91, 126.25, 125.87,121.12, 115.94, 34.31, 21.30; HRMS: calculated for C16H15O (M-H)⁻223.1123; found 223.1120.

Synthesis of I-32

The general procedure was used with prenol (43.1 mg, 0.5 mmol, 50.8 uL),phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 22 hours indicated completeconsumption of prenol. Compound I-32 was isolated as a colorless oil(40.8 mg, 0.251 mmol, 50% yield); R_(f)=0.73 (Hexane/EtOAc=7:3); ¹H NMR(700 MHz, Chloroform-d) δ 7.11 (t, J=7.8 Hz, 2H), 6.87 (t, J=7.4 Hz,1H), 6.80 (d, J=7.8 Hz, 1H), 5.33 (t, J=6.9 Hz, 1H), 5.07 (s, 1H), 3.36(d, J=7.2 Hz, 2H), 1.79 (s, 3H), 1.78 (s, 3H); ¹³C NMR (176 MHz,Chloroform-d) δ 154.44, 134.94, 130.11, 127.68, 126.93, 121.92, 120.90,115.85, 29.96, 25.93, 18.01;

Synthesis of I-33

The general procedure was used with geraniol (77.1 mg, 0.5 mmol, 86.8uL), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 29 hours indicated completeconsumption of geraniol. Compound I-33 was isolated as a colorless oil(83.3 mg, 0.362 mmol, 72% yield); R_(f)=0.73 (Hexane/EtOAc=7:3); ¹H NMR(700 MHz, Chloroform-d) δ 7.11 (d, J=7.6 Hz, 2H), 6.87 (t, J=7.4 Hz,1H), 6.81 (d, J=7.8 Hz, 1H), 5.33 (t, J=7.1 Hz, 1H), 5.09-5.07 (m, 2H),3.37 (d, J=7.2 Hz, 2H), 2.15-2.11 (m, 2H), 2.11-2.07 (m, 2H), 1.78 (s,3H), 1.69 (s, 3H), 1.60 (s, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ154.59, 138.72, 132.13, 130.08, 127.68, 126.94, 123.99, 121.78, 120.87,115.96, 39.84, 29.94, 26.56, 25.84, 17.85, 16.32; HRMS: calculated forC16H21O (M-H)⁻ 229.1592; found 229.1583.

Synthesis of I-34

The general procedure was used with (E)-2-methyl-3-phenylprop-2-en-1-ol(74.1 mg, 0.5 mmol, 71.9 uL), phenol (70.6 mg, 0.75 mmol), acidicalumina (1 g), and 1,2-dichloroethane (5 mL). TLC analysis at 48 hoursindicated complete consumption of geraniol. Compound I-34 was isolatedas a colorless oil (89.2 mg, 0.398 mmol, 80% yield); R_(f)=0.73(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.33 (t, J=7.6 Hz,2H), 7.28-7.24 (m, 3H), 7.22 (t, J=7.3 Hz, 1H), 7.17 (d, J=7.3 Hz, 2H),6.91 (t, J=7.4 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.48 (s, 1H), 5.19 (s,1H), 3.55 (s, 2H), 1.87 (s, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ154.93, 137.83, 137.69, 131.17, 128.98, 128.25, 128.16, 127.03, 126.50,125.02, 120.88, 116.07, 42.11, 17.87; HRMS: calculated for C16H15O(M-H)⁻ 223.1123; found 223.1113.

Synthesis of I-35

The general procedure was used with 3,3-diphenylprop-2-en-1-ol (105.1mg, 0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic alumina (1 g), and1,2-dichloroethane (5 mL). TLC analysis at 48 hours indicated completeconsumption of 3,3-diphenylprop-2-en-1-ol. Compound I-35 was isolated asa colorless oil (100.2 mg, 0.350 mmol, 70% yield); R_(f)=0.64 (100%DCM); ¹H NMR (700 MHz, Chloroform-d) δ 7.43 (q, J=6.4, 5.3 Hz, 2H), 7.37(t, J=7.4 Hz, 1H), 7.27 (qd, J=10.7, 9.8, 6.5 Hz, 7H), 7.19-7.10 (m,2H), 6.90 (q, J=6.6, 5.8 Hz, 1H), 6.79 (dd, J=8.2, 3.0 Hz, 1H), 6.28 (t,J=7.5 Hz, 1H), 4.78-4.69 (m, 1H), 3.48 (dt, J=898.6, 6.5 Hz, 2H); ¹³CNMR (176 MHz, Chloroform-d) δ 153.97, 143.31, 142.27, 139.57, 130.10,130.03, 128.64, 128.29, 127.82, 127.59, 127.51, 127.37, 126.69, 126.52,121.05, 115.64, 30.96; HRMS: calculated for C21H17O (M-H)⁻ 285.1279;found 285.1274.

Synthesis of I-36

The general procedure was used with (E)-3-phenylbut-2-en-1-ol (74.1 mg,0.5 mmol), phenol (70.6 mg, 0.75 mmol), acidic aluminum oxide (1 g) anddichloroethane (5 mL). TLC analysis at 24 hours indicated completeconsumption of (E)-3-phenylbut-2-en-1-ol. Compound I-36 was isolated asa yellow oil (92.3 mg, 0.411 mmol, 82% yield); R_(f)=0.63(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.42-7.39 (m, 2H),7.31 (t, J=7.8 Hz, 2H), 7.25-7.22 (m, 1H), 7.18 (dd, J=7.5, 1.7 Hz, 1H),7.12 (td, J=7.7, 1.7 Hz, 1H), 6.89 (td, J=7.5, 1.2 Hz, 1H), 6.80 (dd,J=7.9, 1.2 Hz, 1H), 5.95 (tt, J=5.8, 1.4 Hz, 1H), 4.88 (s, 1H), 3.57 (d,J=7.3 Hz, 2H), 2.19 (d, J=1.3 Hz, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ154.07, 143.45, 137.09, 130.18, 128.37, 127.72, 127.08, 126.77, 125.89,125.53, 121.08, 115.72, 30.04, 16.16; HRMS: calculated for C16H15O(M-H)⁻ 223.1123; found 223.1115.

Synthesis of I-37

The general procedure was used with phytol (148.3 mg, 0.5 mmol, 174.4uL), phenol (70.6 mg, 0.75 mmol), acidic aluminum oxide (1 g), anddichloroethane (5 mL). TLC analysis at 19 hours indicated completeconsumption of phytol. Compound I-37 was isolated as a colorless oil(121.2 mg, 0.325 mmol, 65% yield); R_(f)=0.43 (Hexane/EtOAc=9:1); ¹H NMR(700 MHz, Chloroform-d) δ 7.14-7.06 (m, 2H), 6.87 (t, J=7.4 Hz, 1H),6.81 (d, J=7.6 Hz, 1H), 5.33 (t, J=7.2 Hz, 1H), 5.10 (s, 1H), 3.38 (d,J=7.0 Hz, 2H), 2.03 (h, J=7.4 Hz, 2H), 1.77 (s, 3H), 1.53 (dt, J=13.3,6.7 Hz, 1H), 1.49-1.42 (m, 1H), 1.42-1.35 (m, 2H), 1.34-1.29 (m, 2H),1.29-1.23 (m, 7H), 1.21-1.17 (m, 1H), 1.16-1.13 (m, 2H), 1.08-1.05 (m,4H), 0.87 (d, J=6.6 Hz, 7H), 0.85 (d, J=3.0 Hz, 4H), 0.84 (d, J=3.0 Hz,3H); ¹³C NMR (176 MHz, Chloroform-d) δ 154.45, 139.14, 129.96, 127.55,126.77, 121.27, 120.72, 115.76, 40.03, 39.39, 37.45, 37.40, 37.31,36.69, 32.81, 32.69, 29.80, 27.99, 25.35, 24.81, 24.48, 22.74, 22.64,19.77, 19.73, 16.21;

Synthesis of I-38

The general procedure was used famesol (222.4 mg, 1 mmol), phenol (140.1mg, 1.5 mmol), acidic aluminum oxide (2 g), and dichloroethane (10 mL).TLC analysis at 40 hours indicated complete consumption of farnesol.Compound I-38 was isolated as a colorless oil (238.4 mg, 0.799 mmol, 80%yield); R_(f)=0.67 (Hexane/EtOAc=8:2); ¹H NMR (700 MHz, Chloroform-d) δ7.11 (d, J=7.4 Hz, 2H), 6.87 (td, J=7.4, 1.3 Hz, 1H), 6.83-6.79 (m, 1H),5.35 (ddt, J=7.2, 5.8, 1.3 Hz, 1H), 5.13-5.07 (m, 3H), 3.38 (d, J=7.3Hz, 2H), 2.15 (q, J=7.3 Hz, 2H), 2.08 (dt, J=23.4, 7.5 Hz, 4H), 1.99(dd, J=9.2, 6.4 Hz, 2H), 1.79 (s, 3H), 1.69 (d, J=1.5 Hz, 3H), 1.61 (d,J=2.1 Hz, 6H); ¹³C NMR (176 MHz, Chloroform-d) δ 154.56, 138.71, 135.68,131.43, 130.06, 127.66, 126.92, 124.51, 123.82, 121.76, 120.86, 115.92,39.83, 39.82, 29.90, 26.83, 26.83, 26.52, 25.84, 17.84, 16.36, 16.19;HRMS: calculated for C21H29O (M-H)⁻ 297.2218; found 297.2221.

Synthesis of I-39

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 2-methoxyphenol (93.1 mg, 0.75 mmol, 83.7 uL), acidic aluminumoxide (1 g), and dichloroethane (5 mL). TLC analysis at 48 hoursindicated cinnamyl alcohol was still existed. Compound I-39 was isolatedas a yellow oil (17.5 mg, 0.073 mmol, 15% yield); R_(f)=0.68(Hexane/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.35 (d, J=7.5 Hz,2H), 7.27 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 6.82-6.75 (m, 3H),6.46 (d, J=15.9 Hz, 1H), 6.40 (dt, J=15.9, 6.7 Hz, 1H), 5.73 (s, 1H),3.90 (s, 3H), 3.57 (d, J=6.6 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ146.56, 143.59, 137.83, 130.88, 128.66, 128.56, 127.05, 126.25, 126.14,122.44, 119.59, 108.87, 56.18, 33.13;

Synthesis of I-40

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), hydroquinone (82.6 mg, 0.75 mmol), acidic aluminum oxide (1 g),and dichloroethane (5 mL). TLC analysis at 48 hours indicated completeconsumption of cinnamyl alcohol. Compound I-40 was isolated as a yellowoil (58.6 mg, 0.259 mmol, 52% yield); R_(f)=0.26 (DCM/MeOH=98:2). ¹H NMR(700 MHz, Chloroform-d) δ 7.35 (d, J=7.5 Hz, 2H), 7.30 (t, J=7.7 Hz,2H), 7.22 (t, J=7.3 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.67 (d, J=3.0 Hz,1H), 6.62 (dd, J=8.5, 3.0 Hz, 1H), 6.50 (d, J=15.9 Hz, 1H), 6.36 (dt,J=15.9, 6.7 Hz, 1H), 4.56 (s, 1H), 4.39 (s, 1H), 3.51 (d, J=6.6 Hz, 2H);¹³C NMR (176 MHz, Chloroform-d) δ 149.63, 148.01, 137.16, 131.86,128.69, 127.67, 127.53, 127.22, 126.35, 117.18, 116.80, 114.32, 34.18;HRMS: calculated for C15H13O2 (M-H)⁻ 225.0916; found 225.0919.

Synthesis of I-41

The general procedure was used with(E)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-ol (89.1 mg, 0.543 mmol),phenol (76.7 mg, 0.815 mmol,), acidic aluminum oxide (1.1 g), anddichloroethane (5.5 mL). TLC analysis at 72 hours indicated completeconsumption of (E)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-ol. CompoundI-41 was isolated a white solid (56.6 mg, 0.236 mmol, 47% yield);R_(f)=0.68 (Hexane/EtOAc=5:5); ¹H NMR (600 MHz, Chloroform-d) δ 7.45(dd, J=7.6, 1.5 Hz, 1H), 7.30 (dd, J=7.4, 1.6 Hz, 1H), 7.28-7.25 (m,1H), 7.22 (td, J=7.4, 1.4 Hz, 1H), 7.17 (dd, J=7.4, 1.7 Hz, 1H), 7.13(td, J=7.7, 1.7 Hz, 1H), 6.90 (td, J=7.5, 1.3 Hz, 1H), 6.83-6.79 (m,2H), 6.27 (dt, J=15.5, 6.6 Hz, 1H), 5.53 (s, 1H), 4.73 (s, 2H), 3.59(dd, J=6.6, 1.7 Hz, 2H), 1.96 (s, 1H); ¹³C NMR (151 MHz, Chloroform-d) δ154.31, 137.35, 136.74, 131.27, 130.64, 128.65, 128.45, 128.09, 127.54,126.55, 125.94, 121.14, 116.07, 63.91, 34.87;

Synthesis of I-42 and I-43

The general procedure was used with cinnamyl alcohol (268.4 mg, 2.0mmol), 3-nitrilphenol (357.4 mg, 0.75 mmol), acidic aluminum oxide (4g), and dichloroethane (20 mL). TLC analysis at 72 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-42 was isolated bycolumn chromatography on C₁₈ as a white solid (47.2 mg, 0.201 mmol, 10%yield). Compound I-43 was isolated by column chromatography on silicagel as a colorless oil (68.9 mg, 0.293 mmol, 15% yield);

Compound I-42, R_(f)=0.78 (Hexane/EtOAc=6:4); ¹H NMR (700 MHz, DMSO-d6)δ 10.30 (s, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.31-7.22 (m, 4H), 7.20 (t,J=7.3 Hz, 1H), 7.16 (dd, J=7.6, 1.6 Hz, 1H), 6.40-6.32 (m, 2H), 3.63 (d,J=5.4 Hz, 2H); ¹³C NMR (176 MHz, DMSO-d6) δ 155.74, 136.71, 130.53,129.29, 128.58, 128.48, 127.25, 126.65, 125.96, 123.40, 120.11, 118.05,112.61, 31.46;

Compound I-43, R_(f)=0.41 (Hexane/EtOAc=8:2); ¹H NMR (700 MHz,Chloroform-d) δ 7.34 (d, J=7.7 Hz, 2H), 7.28 (t, J=7.7 Hz, 2H), 7.20 (t,J=7.3 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.73 (d,J=8.0 Hz, 1H), 6.48 (d, J=15.9 Hz, 1H), 6.33 (dt, J=15.7, 6.4 Hz, 1H),5.03 (s, 1H), 3.74 (d, J=6.4 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ155.01, 137.10, 135.15, 131.36, 128.50, 127.92, 127.31, 126.21, 126.19,124.26, 122.11, 116.85, 114.31;

Synthesis of I-44

The general procedure was used with cinnamyl alcohol (134.2 mg, 1 mmol),3-bromophenol (259.5 mg, 1.5 mmol), acidic aluminum oxide (2 g), anddichloroethane (10 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-44 was isolated as acolorless oil (214.9 mg, 0.75 mmol, 75% yield); R_(f)=0.64(Hexane/EtOAc=8:2); ¹H NMR (600 MHz, Chloroform-d) δ 7.35 (d, J=7.2 Hz,2H), 7.30 (t, J=7.6 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 7.03 (s, 2H), 6.99(s, 1H), 6.49 (d, J=15.8 Hz, 1H), 6.34 (dt, J=15.9, 6.6 Hz, 1H), 3.51(dd, J=6.6, 1.3 Hz, 2H); ¹³C NMR (151 MHz, Chloroform-d) δ 154.94,137.03, 132.00, 131.74, 128.71, 127.60, 127.29, 126.34, 125.07, 124.13,120.62, 119.08, 33.71;

Synthesis of I-45

The general procedure was used with cinnamyl alcohol (134.2 mg, 1 mmol),3-fluorophenol (168.2 mg, 1.5 mmol), acidic aluminum oxide (2 g), anddichloroethane (10 mL). TLC analysis at 24 hours indicated completeconsumption of cinnamyl alcohol. Compound I-45 was isolated as acolorless oil (181.2 mg, 0.79 mmol, 79% yield); R_(f)=0.64(Hexane/EtOAc=8:2)

¹H NMR (700 MHz, Chloroform-d) δ 7.36 (d, J=7.3 Hz, 2H), 7.30 (t, J=7.7Hz, 2H), 7.23 (t, J=7.3 Hz, 1H), 7.10 (dd, J=8.2, 6.7 Hz, 1H), 6.63 (td,J=8.4, 2.5 Hz, 1H), 6.58 (dd, J=9.9, 2.5 Hz, 1H), 6.50 (d, J=15.9 Hz,1H), 6.35 (dt, J=15.8, 6.6 Hz, 1H), 5.14 (s, 1H), 3.53 (d, J=6.5 Hz,2H); ¹³C NMR (176 MHz, Chloroform-d) δ 163.17, 161.79, 155.18, 155.12,137.00, 131.91, 131.26, 131.21, 128.72, 127.69, 127.63, 126.36, 121.40,121.38, 107.81, 107.69, 103.72, 103.59, 33.71;

Synthesis of I-46

The general procedure was used with(E)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-ol (101.2 mg, 0.5 mmol),phenol (70.6 mg, 0.75 mmol), acidic aluminum oxide (1 g), anddichloroethane (5 mL). TLC analysis at 67 hours indicated completeconsumption of (E)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-ol. CompoundI-46 was isolated as a colorless oil (104.1 mg, 0.374 mmol, 75% yield);R_(f)=0.83 (DCM/MeOH=98:2); ¹H NMR (700 MHz, Chloroform-d) δ 7.56 (d,J=8.1 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.21-7.16 (m, 2H), 6.94 (t, J=7.4Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.56-6.52 (m, 2H), 4.84 (s, 1H), 3.61(d, J=4.7 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 153.87, 140.87,131.14, 130.69, 130.08, 129.43, 129.25, 129.06, 128.88, 128.15, 126.43,125.63, 125.61, 125.59, 125.57, 125.52, 121.28, 115.79, 34.01;

Synthesis of I-47

The general procedure was used with(E)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-ol (106.2 mg, 0.5 mmol),phenol (70.6 mg, 0.75 mmol), acidic aluminum oxide (1 g), anddichloroethane (5 mL). TLC analysis at 72 hours indicated completeconsumption of (E)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-ol. CompoundI-47 was isolated as a colorless oil (74.3 mg, 0.258 mmol, 52% yield);R_(f)=0.67 (Hexanez/EtOAc=5:5); ¹H NMR (700 MHz, Chloroform-d) δ7.87-7.84 (m, 2H), 7.51 (dd, J=8.4, 1.3 Hz, 2H), 7.17 (ddd, J=13.9, 7.6,1.6 Hz, 2H), 6.93 (tt, J=7.5, 1.3 Hz, 1H), 6.84 (dd, J=8.0, 1.2 Hz, 1H),6.60 (dtd, J=15.9, 6.6, 1.1 Hz, 1H), 6.50 (dd, J=15.8, 1.5 Hz, 1H), 5.21(s, 1H), 3.62 (dd, J=6.6, 1.5 Hz, 2H), 3.06 (d, J=1.0 Hz, 3H); ¹³C NMR(176 MHz, Chloroform-d) δ 153.87, 143.13, 138.51, 133.20, 130.66,129.36, 128.15, 127.79, 126.92, 125.37, 121.15, 115.73, 44.73, 33.97;

Synthesis of I-48

The general procedure was used with(E)-3-(3-(benzyloxy)phenyl)prop-2-en-1-ol (120.2 mg, 0.5 mmol), phenol(70.6 mg, 0.75 mmol), acidic aluminum oxide (1 g), and dichloroethane (5mL). TLC analysis at 6 hours indicated complete consumption of(E)-3-(3-(benzyloxy)phenyl)prop-2-en-1-ol. Compound I-48 was isolated asa colorless oil (99.7 mg, 0.315 mmol, 63% yield); R_(f)=0.66(Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.44 (d, J=8.1 Hz,2H), 7.39 (t, J=7.5 Hz, 2H), 7.35-7.31 (m, 1H), 7.21 (t, J=7.9 Hz, 1H),7.19-7.14 (m, 2H), 7.00 (s, 1H), 6.97 (dd, J=7.6, 1.5 Hz, 1H), 6.91 (td,J=7.4, 1.3 Hz, 1H), 6.85 (dd, J=8.3, 2.5 Hz, 1H), 6.82 (d, J=7.8 Hz,1H), 6.48 (dd, J=15.8, 1.5 Hz, 1H), 6.39 (dt, J=15.6, 6.5 Hz, 1H), 5.06(s, 2H), 4.91 (s, 1H), 3.57 (d, J=6.6 Hz, 2H); ¹³C NMR (176 MHz,Chloroform-d) δ 159.17, 154.11, 138.77, 137.15, 131.47, 130.61, 129.67,128.72, 128.49, 128.09, 127.63, 125.77, 121.16, 119.31, 115.88, 113.99,112.66, 70.11, 34.16;

Synthesis of I-49

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 3,5-bis(benzyloxy)phenol (229.8 mg, 0.75 mmol), acidic aluminumoxide (1 g), and dichloroethane (5 mL). TLC analysis at 22 hoursindicated complete consumption of cinnamyl alcohol. Compound I-49 wasisolated as an off white solid (143.5 mg, 0.340 mmol, 68% yield);R_(f)=0.63 (Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ7.44-7.36 (m, 8H), 7.34-7.30 (m, 4H), 7.28 (t, J=7.6 Hz, 2H), 7.19 (t,J=7.3 Hz, 1H), 6.47 (d, J=15.8 Hz, 1H), 6.33 (dt, J=15.8, 6.4 Hz, 1H),6.29 (d, J=2.3 Hz, 1H), 6.18 (d, J=2.2 Hz, 1H), 5.04 (d, J=3.2 Hz, 3H),5.01 (s, 2H), 3.59 (dd, J=6.4, 1.8 Hz, 2H); ¹³C NMR (176 MHz,Chloroform-d) δ 158.96, 158.07, 155.81, 137.43, 137.21, 137.02, 130.68,128.75, 128.67, 128.59, 128.47, 128.16, 128.00, 127.69, 127.44, 127.23,126.28, 107.01, 95.27, 93.89, 70.51, 70.29, 26.60;

Synthesis of I-51

The general procedure was used with (E)-3-(4-nitrophenyl)prop-2-en-1-ol(89.6 mg, 0.5 mmol), 3,5-dimethylphenol (93.1 mg, 0.75 mmol), acidicaluminum oxide (1 g), and dichloroethane (5 mL). TLC analysis at 42hours indicated complete consumption of(E)-3-(4-nitrophenyl)prop-2-en-1-ol. Compound I-51 was isolated as ayellow solid (109.2 mg, 0.38 mmol, 77% yield); R_(f)=0.69(Hexanez/EtOAc=5:5); ¹H NMR (700 MHz, Chloroform-d) δ 8.14 (d, J=8.7 Hz,2H), 7.45 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.3 Hz, 1H), 6.58 (dt, J=15.7,6.4 Hz, 1H), 6.53-6.44 (m, 2H), 6.41 (d, J=2.2 Hz, 1H), 4.99 (s, 1H),3.78 (s, 3H), 3.54 (d, J=6.4 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ159.82, 154.64, 146.72, 144.08, 134.23, 131.18, 128.99, 126.72, 124.09,117.35, 106.41, 102.23, 55.51, 33.41;

Synthesis of I-52

The general procedure was used with (E)-3-(4-nitrophenyl)prop-2-en-1-ol(89.6 mg, 0.5 mmol), 3,5-dimethylphenol (91.6 mg, 0.75 mmol), acidicaluminum oxide (1 g), and dichloroethane (5 mL). TLC analysis at 48hours indicated complete consumption of(E)-3-(4-nitrophenyl)prop-2-en-1-ol. Compound I-52 was isolated as ayellow oil (88.1 mg, 0.31 mmol, 62% yield); R_(f)=0.52(Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 8.12 (d, J=8.8 Hz,2H), 7.42 (d, J=8.8 Hz, 2H), 6.64 (s, 1H), 6.54 (dt, J=15.9, 6.1 Hz,1H), 6.50 (s, 1H), 6.38 (d, J=15.9 Hz, 1H), 4.72 (s, 1H), 3.59 (d, J=5.1Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ153.68, 146.59, 144.30, 138.26, 137.41, 133.61, 128.27, 126.64, 124.03,124.01, 120.43, 114.04, 29.72, 21.09, 19.64;

Synthesis of I-53

The general procedure was used with (E)-3-(4-nitrophenyl)prop-2-en-1-ol(89.6 mg, 0.5 mmol), naphthalen-1-ol (108.1 mg, 0.75 mmol), acidicaluminum oxide (1 g), and dichloroethane (5 mL). TLC analysis at 24hours indicated complete consumption of(E)-3-(4-nitrophenyl)prop-2-en-1-ol. Compound I-53 was isolated as ayellow oil (120.1 mg, 0.39 mmol, 79% yield); R_(f)=0.46(Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 8.14 (d, J=8.7 Hz,2H), 8.11 (d, J=8.2 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.52-7.43 (m, 5H),7.28 (d, J=8.4 Hz, 1H), 6.64 (dt, J=15.9, 6.3 Hz, 1H), 6.54 (d, J=15.9Hz, 1H), 5.35 (s, 1H), 3.78 (d, J=6.1 Hz, 2H); ¹³C NMR (176 MHz,Chloroform-d) δ 149.12, 146.89, 143.58, 133.97, 133.13, 129.63, 128.43,128.00, 126.83, 126.12, 125.77, 124.73, 124.12, 121.03, 120.85, 118.04,34.40;

Synthesis of I-54

The general procedure was used with (E)-3-(4-nitrophenyl)prop-2-en-1-ol(89.6 mg, 0.5 mmol), naphthalen-2-ol (108.1 mg, 0.75 mmol), acidicaluminum oxide (1 g), and dichloroethane (5 mL). TLC analysis at 24hours indicated complete consumption of(E)-3-(4-nitrophenyl)prop-2-en-1-ol. Compound I-54 was isolated as ayellow oil (135.0 mg, 0.44 mmol, 88% yield); R_(f)=0.37(Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 8.08 (d, J=8.8 Hz,2H), 7.92 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.8 Hz,1H), 7.53-7.49 (m, 1H), 7.38 (d, J=8.8 Hz, 3H), 7.11 (d, J=8.7 Hz, 1H),6.66 (dt, J=15.9, 6.1 Hz, 1H), 6.44 (d, J=15.9 Hz, 1H), 5.17 (s, 1H),4.04 (dd, J=6.1, 1.4 Hz, 2H); ¹³C NMR (176 MHz, Chloroform-d) δ 151.07,146.62, 144.12, 133.58, 133.40, 129.59, 128.88, 128.85, 128.78, 126.97,126.67, 124.00, 123.51, 123.02, 117.89, 116.64, 28.63;

Synthesis of I-55 and I-56

The general procedure was used with cinnamyl alcohol (268.4 mg, 2.0mmol), 3-nitrophenol (417.3 mg, 3.0 mmol), acidic aluminum oxide (4 g),and dichloroethane (20 mL). TLC analysis at 48 hours indicated completeconsumption of cinnamyl alcohol. Compound I-55 was isolated by columnchromatography on C18 as a brown solid (38.9 mg, 0.17 mmol, 9% yield);Compound I-56 was isolated by column chromatography on C₁₈ as a yellowsolid (62.7 mg, 0.28 mmol, 14% yield); Compound I-55, R_(f)=0.61(Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ 7.78 (d, J=8.3 Hz,1H), 7.69 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.33-7.30 (m, 4H), 7.24 (t,J=7.3 Hz, 1H), 6.53 (d, J=15.9 Hz, 1H), 6.38-6.31 (m, 1H), 5.54 (s, 1H),3.64 (d, J=6.7 Hz, 2H); 13C NMR (176 MHz, Chloroform-d) δ 154.42,147.70, 136.77, 134.06, 132.94, 130.91, 128.79, 127.87, 126.39, 125.95,116.27, 110.79, 34.06;

Compound I-56, Rf=0.37 (Hexanez/EtOAc=7:3); 1H NMR (700 MHz,Chloroform-d) δ 7.45 (d, J=8.1 Hz, 1H), 7.34 (d, J=7.7 Hz, 2H), 7.28 (t,J=7.4 Hz, 2H), 7.27-7.23 (m, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 6.55 (d, J=15.8 Hz, 1H), 6.41-6.35 (m, 1H), 5.46 (s, 1H), 3.75(d, J=6.5 Hz, 2H); 13C NMR (176 MHz, Chloroform-d) δ 155.45, 151.12,136.93, 132.35, 128.68, 127.89, 127.68, 126.43, 125.88, 120.98, 120.23,117.03, 29.52;

Synthesis of I-57

The general procedure was used with(E)-3-(3-(benzyloxy)phenyl)prop-2-en-1-ol (120.2 mg, 0.5 mmol),3,5-bis(benzyloxy)phenol (229.8 mg, 0.75 mmol), acidic aluminum oxide (1g), and dichloroethane (5 mL). TLC analysis at 22 hours indicatedcomplete consumption of (E)-3-(3-(benzyloxy)phenyl)prop-2-en-1-ol.Compound I-57 was isolated as a yellow oil (210.1 mg, 0.355 mmol, 71%yield); R_(f)=0.45 (Hexanez/EtOAc=7:3); ¹H NMR (700 MHz, Chloroform-d) δ7.44-7.30 (m, 16H), 7.19 (t, J=7.9 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H), 6.93(d, J=7.6 Hz, 1H), 6.82 (dd, J=8.2, 2.5 Hz, 1H), 6.43 (d, J=15.8 Hz,1H), 6.32 (dt, J=15.9, 6.4 Hz, 1H), 6.29 (d, J=2.3 Hz, 1H), 6.17 (d,J=2.3 Hz, 1H), 5.05 (s, 2H), 5.03 (s, 2H), 5.01 (s, 2H), 3.60-3.56 (m,2H); ¹³C NMR (176 MHz, Chloroform-d) 159.13, 158.96, 158.08, 155.77,138.99, 137.20, 137.01, 130.50, 129.57, 128.90, 128.75, 128.70, 128.67,128.16, 128.06, 128.00, 127.68, 127.62, 127.44, 119.28, 113.83, 112.53,106.97, 95.26, 93.87, 70.50, 70.29, 70.08, 26.56;

Synthesis of I-58

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), beta-estradiol (204.3 mg, 0.75 mmol), acidic aluminum oxide (1g), and dichloroethane (5 mL). TLC analysis at 18 hours indicatedcomplete consumption of cinnamyl alcohol. Compound I-58 was isolated asa white solid (159.4 mg, 0.410 mmol, 82% yield); R_(f)=0.36(DCM/MeOH=98:2); ¹H NMR (700 MHz, Chloroform-d) δ 7.35 (dt, J=8.1, 1.8Hz, 2H), 7.29 (dd, J=8.5, 6.9 Hz, 2H), 7.23-7.18 (m, 1H), 7.08 (s, 1H),6.56 (s, 1H), 6.51 (dt, J=15.9, 1.7 Hz, 1H), 6.38 (dt, J=15.9, 6.7 Hz,1H), 4.86 (s, 1H), 3.73 (t, J=8.6 Hz, 1H), 3.58-3.48 (m, 2H), 2.87-2.76(m, 2H), 2.32 (dtd, J=13.5, 4.2, 2.6 Hz, 1H), 2.20-2.15 (m, 1H), 2.12(dtd, J=13.4, 9.3, 5.8 Hz, 1H), 1.94 (ddd, J=12.7, 4.0, 2.8 Hz, 1H),1.89-1.85 (m, 1H), 1.73-1.67 (m, 1H), 1.59 (s, 1H), 1.53-1.26 (m, 5H),1.19 (ddd, J=12.4, 11.0, 7.3 Hz, 1H), 0.78 (s, 3H); ¹³C NMR (176 MHz,Chloroform-d) δ 152.00, 137.34, 136.61, 132.96, 131.31, 128.64, 128.57,127.54, 127.37, 126.33, 123.03, 115.94, 82.09, 50.17, 44.10, 43.39,39.01, 36.85, 34.40, 30.73, 29.40, 27.38, 26.54, 23.27, 11.22;

Synthesis of I-59

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), 17-alpha-ethynylestradiol (222.3 mg, 0.75 mmol), acidic aluminumoxide (1 g), and dichloroethane (5 mL). TLC analysis at 21 hoursindicated complete consumption of cinnamyl alcohol. Compound I-59 wasisolated as a white solid (143.2 mg, 0.347 mmol, 69% yield); R_(f)=0.80(Hexane/EtOAc=6:4); ¹H NMR (700 MHz, Chloroform-d) δ 7.35 (d, J=7.3 Hz,2H), 7.29 (t, J=7.7 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.08 (s, 1H), 6.56(s, 1H), 6.51 (d, J=15.9 Hz, 1H), 6.38 (dt, J=15.9, 6.7 Hz, 1H), 4.85(s, 1H), 3.53 (m, 2H), 2.84-2.78 (m, 2H), 2.60 (s, 1H), 2.40-2.31 (m,2H), 2.25-2.19 (m, 1H), 2.05-2.00 (m, 1H), 1.95 (s, 1H), 1.92-1.85 (m,2H), 1.81-1.78 (m, 1H), 1.73-1.68 (m, 2H), 1.53-1.32 (m, 4H); ¹³C NMR(176 MHz, Chloroform-d) δ 152.00, 137.31, 136.61, 132.89, 131.34,128.64, 128.54, 127.58, 127.38, 126.33, 123.03, 115.95, 87.63, 80.06,74.20, 49.60, 43.67, 39.58, 39.10, 34.41, 32.87, 29.41, 27.37, 26.61,22.94, 12.84;

Synthesis of I-60

The general procedure was used with cinnamyl alcohol (67.1 mg, 0.5mmol), estrone (202.8 mg, 0.75 mmol), acidic aluminum oxide (1 g), anddichloroethane (5 mL). TLC analysis at 21 hours indicated completeconsumption of cinnamyl alcohol. Compound I-60 was isolated as acolorless oil (119.9 mg, 0.310 mmol, 62% yield); R_(f)=0.84(Hexane/EtOAc=6:4); ¹H NMR (700 MHz, Chloroform-d) δ 7.35 (d, J=7.3 Hz,2H), 7.29 (t, J=7.6 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.08 (s, 1H), 6.58(s, 1H), 6.51 (d, J=15.9 Hz, 1H), 6.37 (dt, J=15.7, 6.6 Hz, 1H), 4.98(s, 1H), 3.58-3.49 (m, 2H), 2.91-2.81 (m, 2H), 2.51 (dd, J=19.2, 8.6 Hz,1H), 2.43-2.38 (m, 1H), 2.24 (dt, J=11.1, 5.8 Hz, 1H), 2.19-2.11 (m,1H), 2.05 (ddd, J=13.3, 8.7, 5.8 Hz, 2H), 2.02-1.92 (m, 2H), 1.64-1.40(m, 6H), 0.91 (s, 3H); ¹³C NMR (176 MHz, Chloroform-d) δ 221.35, 152.18,137.29, 136.36, 132.33, 131.36, 128.64, 128.44, 127.54, 127.40, 126.32,123.24, 115.97, 50.54, 48.18, 44.12, 38.53, 36.03, 34.

Example 6: Synthesis of an Exemplary Anti-Inflammatory Drug Candidate(L-651896)

To further illustrate the utility of the method of the application,synthetic target L-651896 (I-125), an anti-inflammatory drug candidatedeveloped at Merck, was selected.⁶³ The reported synthesis of I-125 wasaccomplished in seven steps from phenol II-4 wherein and allylic alcoholIII-4 (Scheme 8).⁶⁴ When the same two substrates were subjected to thealumina-templated allylation reaction of the application=, the finalproduct (I-125) was obtained in one step with an isolated yield of 49%.

Synthesis of I-125 Step 1

To a solution of 2-naphthol (2 g, 13.9 mmol) in an acetonitrile-water(100 mL, 1:1, v/v) mixture was incrementally added Oxone (6.346 g, 41.7mmol). After completion of the reaction, based on TLC analysis, thereaction mixture was extracted with ethyl acetate multiple times. Thecombined organic extract was dried over anhydrous Na₂SO₄ andconcentrated in vacuum to give a crude yellow solid product(E)-2-(2-carboxyvinyl)benzoic acid. The crude product was directly usedwithout purification for the next step. A catalytic amount ofconcentrated H₂SO₄ was slowly added to the solution of(E)-2-(2-carboxyvinyl)benzoic acid in MeOH, the mixture was stirred atreflux for 24 hours and then concentrated in vacuo, the residue wasdiluted with DCM and washed with saturated NaHCO₃, brine and dried overNa₂SO₄ to give a crude yellow oil methyl(E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)benzoate. Crude oil was usedwithout purification for the next step. The crude oil from last step(379 mg, 1.72 mmol, 1 equiv.) was dissolved in anhydrous DCM (18 mL) andcooled to −78° C. under Argon. DIABAL-H (6.145 mL, 7.6 mmol) wasdropwise added to the solution, the reaction mixture was kept at −78° C.under Argon with stirring for 2 hours and then quenched by 10% NaOH (18mL) at −78° C. The reaction mixture was warmed to room temperature withstirring for another 1 hour, and then was extracted by DCM (3×50 mL).Organic layers were combined, washed with brine, dried over Na₂SO₄,concentrated under reduced pressure and the residue purified by C18column chromatography, eluted with CH₃CN/H₂O to afford compound III-4(E)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-ol as a yellow oil.

¹H NMR (700 MHz, Chloroform-d) δ 7.40 (d, J=7.6 Hz, 1H), 7.22 (t, J=7.7Hz, 2H), 7.20-7.16 (m, 1H), 6.82 (d, J=15.8 Hz, 1H), 6.15 (dt, J=1.8,5.2 Hz, 1H), 4.58 (s, 2H), 4.16 (dt, J=5.2, 1.4 Hz, 2H), 3.92 (s, 2H);

¹³C NMR (176 MHz, Chloroform-d) δ 137.5, 136.1, 131.0, 129.0, 128.2,127.6, 127.2, 126.2, 63.1, 63.0. This spectral data is consistent with aprevious literature report.⁶⁴

Step 2

2,3-dihydro-1-benzofuran-5-carbaldehyde (500 mg, 3.37 mmol) wasdissolved in 5 mL anhydrous DCM in a 50 mL round bottom flask chargedwith a magnetic stir bar. The flask was flushed with nitrogen and cooledto 0° C. in an ice bath. m-CPBA (1.187 g, 5.16 mmol) was added to thesolution and the reaction mixture was stirred at 0° C. for 5 minutes,then warmed to room temperature with stirring for another 2 hours. Thereaction mixture was washed with saturated Na₂SO₃ solution and extractedby DCM (3×50 mL), organic layers were combined, dried over Na₂SO₄, andconcentrated in vacuo. The crude residue was dissolved in a MeOH-6M HCl(11 mL, 10:1, v/v) mixture and stirred under nitrogen for 16 hours. Themixture was washed by saturated NaHCO₃, brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel, eluted with EtOAc/Hexane to yield compound84 2,3-dihydrobenzofuran-5-ol as a white solid.

¹H NMR (700 MHz, Chloroform-d) δ 6.72 (dt, J=2.5, 1.1 Hz, 1H), 6.63 (d,J=8.5 Hz, 1H), 6.56 (dd, J=8.5, 2.6 Hz, 1H), 4.55 (s, 1H), 4.53 (t,J=8.6 Hz, 2H), 3.16 (t, J=8.6 Hz, 2H);

¹³C NMR (176 MHz, Chloroform-d) δ 154.2, 149.7, 128.3, 114.3, 112.5,109.4, 71.4, 30.3 This spectral data is consistent with a previousliterature report.⁶⁴

Step 3: Synthesis of Compound 85 (L-651896, I-125)

General Procedure as described in Example 4 was used with(E)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-ol (130.0 mg, 0.79 mmol),2,3-dihydrobenzofuran-5-ol (161.7 mg, 1.19 mmol), acidic aluminum oxide(1.6 g), and dichloroethane (8 mL). TLC analysis at 16 hours indicatedcomplete consumption of (E)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-ol.Compound I-125 (L-651896) was isolated a white solid (110.2 mg, 0.39mmol, 49% yield); R_(f)=0.50 (Hexane/EtOAc=5:5); ¹H NMR (700 MHz,Acetone-d6) δ 7.70 (s, 1H), 7.47-7.44 (m, 1H), 7.42-7.39 (m, 1H),7.22-7.16 (m, 2H), 6.81 (d, J=15.6 Hz, 1H), 6.75 (s, 1H), 6.56 (s, 1H),6.29 (dt, J=15.6, 7.0 Hz, 1H), 4.70 (d, J=5.4 Hz, 2H), 4.42 (t, J=8.6Hz, 2H), 4.08 (t, J=5.5 Hz, 1H), 3.52-3.47 (m, 2H), 3.13-3.06 (m, 2H);¹³C NMR (176 MHz, Acetone-d6) δ 154.5, 149.4, 139.6, 137.0, 131.8,128.4, 128.4, 128.0, 127.6, 126.5, 126.3, 126.3, 112.8, 110.6, 71.5,62.7, 34.6, 30.7; This spectral data is consistent with a previousliterature report.⁶⁴

Example 7

The effect of various commercially available reagents instead of or inaddition to alumina on an exemplary process of the application wasinvestigated.

General Reaction Procedure: Geraniol (III-1, 1.0 equiv.) was charged toa microwave reaction vial in 1,2-dichloroethane (10 mL/mmol of geraniol)followed by 1-naphthol (II-5, 1.5 equiv.) and additive. The suspensionwas stirred in a Microwave Synthesis Reactor at 150° C. for 10 minutes.The reaction mixture was cooled and filtered through Celite®. The solidswere washed with EtOAc (3×10 mL) and the filtrates combined andconcentrated in vacuo. The yield of product (I-129) was determined by ¹HNMR analysis of the crude reaction mixture using 1,2-dibromomethane asan internal standard.

TABLE 7

Yield of Recovered Product^(a) Naphthol Additive (%) (%) none 0 >95Al₂O₃, Acidic (1 g, 2 g/mmol) 74 33 Al₂O₃, Acidic (0.5 g, 1 g/mmol) 3673 Al(OiPr)₃ (0.16 g, 1.5 equiv.) 63 20 MgSO₄ (0.19 g, 3 equiv.) + Al₂O₃52 33 (1 g, 2 g/mmol) MgSO₄ (0.5 g, 1 g/mmol) + Al₂O₃ (0.5 g, 51 61 1g/mmol) MgSO₄ (0.58 g, 1 g/mmol) + Al₂O₃ (0.58 g, 62 25 1 g/mmol)^(b)MgSO₄ (1 g, 2 g/mmol) 18 88 Montmorillonite K10 (1 g, 2 g/mmol) 12 83Kaolinite (1 g, 2 g/mmol) 12 72 MsOH (0.057 g, 1 equiv.) <5 40 V₂O₅(0.16 g, 1.6 equiv.) <5 80 NaOTf (0.13 g, 1.5 equiv.) <5 81 3Å MolecularSieves (1 g, 2 g/mmol) <5 >95 Al(OTf)₃ (0.39 g, 1.5 equiv.) 0 40 LiOTf(0.12 g, 1.5 equiv.) 0 57 SnCl₄ (0.16 g, 1.0 equiv.) 0 58 ZnCl₂ (1 g, 2g/mmol) 0 84 AlCl₃ (0.093 g, 1.3 equiv) 0 87 AlCl₃ (0.099 g, 1.5equiv.) + Al₂O₃ (1 g, 0 92 2 g/mmol) AlCl₃ (0.11 g, 1.7 equiv.) +geranyl bromide^(c) 0 95 AcOH (0.034 g, 1 equiv.) 0 >95 CoCl₂ • 6H₂O(0.23 g, 1.5 equiv.) 0 >95 Cs₂CO₃ (1 g, 2 g/mmol) 0 >95 KCl (1 g, 2g/mmol) 0 >95 LiCl (1 g, 2 g/mmol) 0 >95 MgO (0.52 g, 1 g/mmol) 0 >95NaCl (1 g, 2 g/mmol) 0 >95 TiCl₄ (0.15 g, 1.3 equiv.) 0 >95 Ti(II)O₂(0.051 g, 1.5 equiv.) 0 >95 Ti(IV)O₂ (0.70 g, 1.5 equiv.) 0 >95 SiO₂ (1g, 2 g/mmol) 0 >95 ZrO₂ (0.10 g, 1.5 equiv.) 0 >95 Zeolite (1 g, 2g/mmol) 0 >95 ^(a)Yields determined using 1H NMR with an internalstandard ^(b)Reaction was completed in flask refluxing in1,2-dichloroethane using an oil bath (see procedure below). ^(c)Reactionused geranyl bromide in substitution of geraniol.

Example 8 Synthesis of Exemplary Compounds of Formula (I)

Synthesis of I-126

To a stirring solution of 150 mg (1.74 mmol) of prenol (1 equiv.) and517.7 mg (2.61 mmol) of 4-(1,3-dithiolan-2-yl)phenol (1.5 equiv.) wasadded 1742.8 mg of acidic alumina (1 g/mmol of prenol) in 9 mL of1,2-dichloroethane (0.2 M). The crude mixture was heated to 80° C. andstirred for 24 hours. The reaction was cooled down to room temperature,filtered through a Celite® pad and rinsed with EtOAc. The filtrate wasconcentrated under reduced pressure and purified by normal phasechromatography onto a 24 g SiO₂ column, eluted from 2 to 20%EtOAc/hexanes over 20 CVs. 165.4 mg (36% yield) of the desired productwas recovered as a yellow oil; ¹H NMR (400 MHz, Chloroform-c) δ 7.29(dd, J=8.3, 2.4 Hz, 1H), 7.25 (d, J=2.3 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H),5.61 (s, 1H), 5.31 (dddt, J=7.2, 5.8, 2.9, 1.4 Hz, 1H), 5.12 (s, 1H),3.55-3.46 (m, 2H), 3.34 (ddd, J=7.6, 6.0, 3.9 Hz, 4H), 1.78 (dd, J=3.2,1.4 Hz, 6H).

Synthesis of I-127

To a stirring solution of 226 mg (1.46 mmol) of geraniol (2 equiv.) and100 mg (0.73 mmol) of 4-hydroxy actetophenone (1 equiv.) was added 2.94g of acidic alumina (2 g/mmol of geraniol) in 5 mL of 1,2dichloroethane. The mixture was heated to 80° C. and stirred for 24hours. The reaction was cooled down to room temperature, filteredthrough a Celite® pad and rinsed with EtOAc and MeOH. The filtrate wasconcentrated under reduced pressure and purified by normal phasechromatography with a gradient up to 30% EtOAc/Hex. 21.0 mg (10% yield)of the desired product was recovered as a white solid; 1H NMR (400 MHz,Chloroform-d) δ 7.78 (t, J=2.1 Hz, 1H), 7.75 (d, J=2.3 Hz, 1H), 6.87 (d,J=8.2 Hz, 1H), 6.44 (s, 1H), 5.37-5.28 (m, 1H), 5.07 (tdd, J=5.3, 2.8,1.4 Hz, 1H), 3.41 (d, J=7.2 Hz, 2H), 2.55 (s, 3H), 2.15-2.05 (m, 4H),1.77 (d, J=1.3 Hz, 3H), 1.68 (s, 3H), 1.59 (d, J=1.3 Hz, 3H).

Synthesis of I-128

To a stirring solution of 226 mg (1.46 mmol) of geraniol (2 equiv.) and100 mg (0.73 mmol) of 4-hydroxyactetophenone (1 equiv.) was added 2.94 gof acidic alumina (2 g/mmol of geraniol) in 5 mL of 1,2 dichloroethane.The mixture was heated to 80° C. and stirred for 24 hours. The reactionwas cooled down to room temperature, filtered through a Celite® pad andrinsed with EtOAc and MeOH. The filtrate was concentrated under reducedpressure and purified by normal phase chromatography with a gradient upto 25% EtOAc/Hex. 51.4 mg (17% yield) of the desired product wasrecovered as a white solid; 1H NMR (400 MHz, Chloroform-d) δ 7.26 (s,2H), 4.97-4.92 (m, 2H), 4.70 (tq, J=5.0, 1.6 Hz, 2H), 3.01 (d, J=7.2 Hz,4H), 2.15 (s, 3H), 1.78-1.68 (m, 12H), 1.39 (d, J=1.4 Hz, 6H), 1.30 (d,J=1.4 Hz, 6H), 1.22 (d, J=1.5 Hz, 6H).

Synthesis of I-129: Microwave Reaction

Geraniol (87.1 mg, 0.565 mmol) was charged to a vial in1,2-dichloroethane (5 mL) followed by 1-naphthol (122 mg, 0.846 mmol)and acidic aluminum oxide (1.02 g). The suspension was stirred in aMicrowave Synthesis Reactor at 150° C. for 10 minutes. The reactionmixture was cooled and filtered through Celite®. The solids were washedwith EtOAc (3×10 mL) and the filtrates combined and concentrated invacuo. The yield of product was determined by 1H NMR analysis of thecrude reaction mixture using 1,2-dibromomethane (118 mg, 0.679 mmol) asan internal standard; NMR Yield=74% (0.417 mmol); 1H NMR (700 MHz,Chloroform-d)=δ 8.07-8.04 (m, 1H), 7.65-7.63 (m, 1H), 7.35-7.29 (m, 2H),7.25 (d, J=8.1 Hz, 1H), 7.09 (d, J=8.3, 1H), 5.29 (m, 1H), 4.96 (m, 1H),3.40 (d, J=7.2 Hz, 2H), 2.03 (m, 4H), 1.72 (s, 3H), 1.59 (s, 3H), 1.50(s, 3H).

Synthesis of I-129: Microwave Reaction with Aluminum Isopropoxide

Geraniol (84.4 mg, 0.547 mmol) was charged to a reaction vial in1,2-dichloroethane (5 mL) followed by 1-naphthol (124 mg, 0.861 mmol)and aluminum isopropoxide (165 mg, 0.810 mmol). The suspension wasstirred in a Microwave Synthesis Reactor at 150° C. for 10 minutes. Thereaction mixture was cooled and filtered through Celite®. The solidswere washed with EtOAc (3×10 mL) and the filtrates combined andconcentrated in vacuo. The yield of product was determined by 1H NMRanalysis of the crude reaction mixture using 1,2-dibromomethane (69.8mg, 0.402 mmol) as an internal standard; NMR Yield=63% (0.347 mmol); 1HNMR (700 MHz, Chloroform-d)=δ 8.07-8.04 (m, 1H), 7.65-7.63 (m, 1H),7.35-7.29 (m, 2H), 7.25 (d, J=8.1 Hz, 1H), 7.09 (d, J=8.3, 1H), 5.29 (m,1H), 4.96 (m, 1H), 3.40 (d, J=7.2 Hz, 2H), 2.03 (m, 4H), 1.72 (s, 3H),1.59 (s, 3H), 1.50 (s, 3H).

Synthesis of I-129: Alumina and Magnesium Sulfate

Geraniol (85.7 mg, 0.556 mmol) was charged to a 50 mL RBF in1,2-dichloroethane (5 mL) followed by 1-naphthol (125 mg, 0.867 mmol),acidic aluminum oxide (0.583 mg, 1 g/mmol) and magnesium sulfate (0.586g, 1 g/mmol). The suspension was stirred in an oil bath at refluxingtemperature (84° C.). TLC analysis at 24 hours indicated completeconsumption of geraniol. The reaction mixture was cooled and filteredthrough Celite®. The solids were washed with EtOAc (3×10 mL) and thefiltrates combined and concentrated in vacuo. The yield of product wasdetermined by 1H NMR analysis of the crude reaction mixture using1,2-dibromomethane (73.0 mg, 0.420 mmol) as an internal standard; NMRYield=63% (0.347 mmol); 1H NMR (700 MHz, Chloroform-d)=δ 8.07-8.04 (m,1H), 7.65-7.63 (m, 1H), 7.35-7.29 (m, 2H), 7.25 (d, J=8.1 Hz, 1H), 7.09(d, J=8.3, 1H), 5.29 (m, 1H), 4.96 (m, 1H), 3.40 (d, J=7.2 Hz, 2H), 2.03(m, 4H), 1.72 (s, 3H), 1.59 (s, 3H), 1.50 (s, 3H).

Synthesis of I-1: No Chromatography

To a round bottom flask containing DCE (0.2M; pre-dried over 4A MS) wasadded acidic alumina (2 g/mmol of alcohol) which was pre-dried undervacuum at 200° C. and stored in desiccator. To the reaction mixture wasadded olivetol (3.0 equiv.) followed by geraniol (1.0 equiv.) and themixture was heated to reflux for one hour. The reaction mixture wasfiltered through a frit funnel under vacuum eluting with DCE. Thesolution was concentrated and the crude oil was filtered through asilica pad eluting with 5% ethyl acetate/hexanes providing CBG as ayellow-orange solid (70%). The solid can be recrystallized using hotheptane, allowed to cool to room temperature and placed in freezerovernight. The white solids were filtered under vacuum and washed withcold heptane providing pure CBG (88% based of crude yield).

Synthesis of I-1: Aluminum Isopropoxide

Geraniol (80.8 mg, 0.524 mmol) was charged to a reaction vial in1,2-dichloroethane (5 mL) followed by olivetol (146 mg, 0.808 mmol) andaluminum isopropoxide (158 mg, 0.775 mmol). The suspension was stirredin a Microwave Synthesis Reactor at 150° C. for 10 minutes. The reactionmixture was cooled and filtered through Celite®. The solids were washedwith EtOAc (3×10 mL) and the filtrates combined and concentrated invacuo. The yields of Cannabigerol and (55854-24-5) were determined by 1HNMR analysis of the crude reaction mixture using 1,2-dibromomethane(70.6 mg, 0.406 mmol) as an internal standard; NMR Yield=CBG: 21% (0.108mmol)

Synthesis of I-110: Arachidin 2

To a round bottom flask containing MeCN (0.08M, pre-dried over 4A MS)was added acidic alumina (2 g/mmol of alcohol) which was pre-dried undervacuum at 200° C. and stored in desiccator. To the stirring mixture wasadded resveratrol (5.0 equiv.) followed by geraniol (1.0 equiv.) and thereaction was heated to reflux for 24 hrs. The reaction mixture wasfiltered through a Celite® pad eluting with ethyl acetate, concentratedand purified by column chromatography providing Arachidin 2 as anoff-white solid (42%); 1H NMR (700 MHz, DMSO) δ 9.51 (s, 1H), 9.07 (s,2H), 7.38 (d, J=8.6 Hz, 2H), 6.78 (d, J=1.9 Hz, 2H), 6.75 (d, J=8.4 Hz,2H), 6.44 (s, 2H), 5.18 (t, J=7.0 Hz, 1H), 5.05 (tdd, J=5.7, 2.9, 1.5Hz, 1H), 3.17 (d, J=7.1 Hz, 2H), 2.01-1.98 (m, 2H), 1.91-1.89 (m, 2H),1.71 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H).

Synthesis of I-111: Amorphastilbol

To a round bottom flask containing DCE (0.08M; pre-dried over 4A MS) wasadded acidic alumina (2 g/mmol of phenol) which was pre-dried undervacuum at 200° C. and stored in desiccator. To the reaction mixture wasadded pinosylvin (3.0 equiv.) followed by geraniol (1.0 equiv.) and thereaction mixture was heated to reflux overnight. The reaction mixturewas cooled to room temperature and filtered through a Celite® padeluting with ethylacetate. The solution was concentrated and purified bycolumn chromatography providing Amorphastilbol as a beige solid (70%);1H NMR (400 MHz, CDCl₃) δ 7.49-7.47 (m, 2H), 7.35 (t, J=7.5 Hz, 2H),7.27-7.23 (m, 1H), 7.02, 6.93 (ABq, J=16.3 Hz, 2H), 6.59 (s, 2H),5.30-5.26 (m, 1H), 5.08-5.04 (m, 3H), 3.44 (d, J=7.0 Hz, 2H), 2.13-2.06(m, 4H), 1.83 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H).

Synthesis of I-114

To a round bottom flask containing DCE (0.08M; pre-dried over 4A MS) wasadded acidic alumina (2 g/mmol of alcohol) which was pre-dried undervacuum at 200° C. and stored in desiccator. To the reaction mixture wasadded dihydropinosylvin (1.0 equiv.) followed by geraniol (1.0 equiv.)and the mixture was heated to reflux overnight. The reaction mixture wascooled to room temperature and filtered through a Celite® pad elutingwith ethyl acetate. The solution was concentrated and purified by columnchromatography providing the desired compound as a white solid (30%); 1HNMR (700 MHz, CDCl₃) δ 7.32-7.27 (m, 2H), 7.23-7.19 (m, 3H), 6.28 (s,2H), 5.31-5.27 (m, 1H), 5.10-5.05 (m, 3H), 3.42 (d, J=7.1 Hz, 2H),2.91-2.85 (m, 2H), 2.82-2.76 (m, 2H), 2.16-2.05 (m, 4H), 1.83 (s, 3H),1.70 (s, 3H), 1.61 (s, 3H).

Synthesis of I-115: Chiricanin A

To a round bottom flask containing DCE (0.08M; pre-dried over 4A MS) wasadded acidic alumina (2 g/mmol of phenol) which was pre-dried undervacuum at 200° C. and stored in desiccator. To the stirring mixture wasadded pinosylvin (3 equiv.) followed by prenol (1.0 equiv.) and thereaction mixture was stirred at reflux overnight. Once complete, basedon TLC analysis, the reaction mixture was filtered through a Celite® padeluting with ethyl acetate, concentrated and purified by columnchromatography providing Chiricanin A as a beige solid (62%); 1H NMR(700 MHz, CDCl₃) δ 7.48 (br d, J=7.3 Hz, 2H), 7.35 (t, J=7.7 Hz, 2H),7.27-7.24 (m, 1H), 7.00, 6.93 (ABq, J=16.3 Hz, 2H), 6.59 (s, 2H), 5.28(ddt, J=7.1, 5.7, 1.4 Hz, 1H), 5.14 (br s, 2H), 3.43 (d, J=7.1 Hz, 2H),1.84 (s, 3H), 1.77 (s, 3H).

Synthesis of I-131

Prenol (1 equiv.) and the isobutyrylphloroglucinol (1.5 equiv.) weredissolved in EtOAc (0.2 M). Acidic alumina (2 g/mmol) was added to thereaction mixture and was allowed to stir at reflux for 24 h. The crudemixture was filtered over a Celite® pad, rinsed with EtOAc andconcentrated to dryness under vacuum. The crude reaction mixture waspurified by reverse phase chromatography on C18 column with gradientelution using CH₃CN and H₂O. Purification afforded 22.4 mg (36% yield)of the desired product as a yellow solid; 1H NMR (700 MHz, Chloroform-d)δ 5.82 (s, 1H), 5.78 (s, 1H), 5.25 (tp, J=7.2, 1.4 Hz, 1H), 3.86 (hept,J=6.7 Hz, 1H), 3.37 (d, J=7.1, 2H), 1.83 (s, 3H), 1.78 (d, J=1.4 Hz,3H), 1.18 (d, J=6.8 Hz, 6H); 13C NMR (176 MHz, Chloroform-d) δ 210.52,160.50, 136.47, 121.49, 105.65, 104.20, 95.42, 60.43, 39.34, 25.85,21.71, 21.07, 19.30, 17.92, 14.21.

Synthesis of I-132

Prenol (1 equiv.) and the isobutyrylphloroglucinol (1.5 equiv.) weredissolved in EtOAc (0.2 M). Acidic alumina (2 g/mmol) was added to thereaction mixture and was allowed to stir at reflux for 24 h. The crudemixture was filtered over a Celite® pad, rinsed with EtOAc andconcentrated to dryness under vacuum. The crude reaction mixture waspurified by reverse phase chromatography on C18 column with gradientelution using CH₃CN and H₂O. Purification afforded 238.9 mg (37% yield)of the desired product as a yellow oil; 1H NMR (700 MHz, Chloroform-d):δ 11.54 (br. s, 1H), 8.35 (br. s, 1H), 5.95 (s, 1H), 5.84 (s, 1H), 5.25(t, J=7.2 Hz, 1H), 5.05 (t, J=6.2 Hz, 1H), 3.88 (hept, J=6.8 Hz, 1H),3.38 (d, J=7.2 Hz, 2H), 2.11 (t, J=6.8 Hz, 2H), 2.09 (m, 2H), 1.81 (s,3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.17 (d, J=6.8 Hz, 6H); 13C NMR (176MHz, Chloroform-d): δ 210.76, 160.86, 140.35, 132.35, 121.58, 105.77,104.34, 95.64, 39.83, 39.45, 21.78, 19.44, 17.86, 16.38.

Synthesis of I-133

Prenol (1 equiv.) and the acylphloroglucinol substrate (1.5 equiv.) weredissolved in EtOAc (0.2 M). Acidic alumina (2 g/mmol) was added to thereaction mixture and was allowed to stir at reflux for 24 h. The crudemixture was filtered over a Celite® pad, rinsed with EtOAc andconcentrated to dryness under vacuum. The crude reaction mixture waspurified by reverse phase chromatography on C18 column with gradientelution using CH₃CN and H₂O. Purification afforded 109.1 mg (27% yield)of the desired product as a yellow solid; 1H NMR (700 MHz, Chloroform-d)δ 5.86-5.79 (m, 2H), 5.28-5.23 (m, 1H), 3.76-3.69 (m, 1H), 3.40-3.34 (m,2H), 1.86-1.81 (m, 3H), 1.78 (s, 3H), 1.45-1.37 (m, 1H), 1.19-1.14 (m,3H), 0.95-0.88 (m, 3H); 13C NMR (176 MHz, Chloroform-d) δ 210.33,160.51, 136.43, 121.50, 105.66, 104.71, 95.41, 46.01, 26.93, 25.85,21.70, 17.92, 16.71, 11.97.

Synthesis of I-134

Geraniol (300 mg, 1.95 mmol, 1 equiv.) and the acylphloroglucinolsubstrate (1.5 equiv.) were dissolved in EtOAc (0.2 M). Acidic alumina(2 g/mmol) was added to the reaction mixture and was allowed to stir atreflux for 24 h. The crude mixture was filtered over a Celite® pad,rinsed with EtOAc and concentrated to dryness under vacuum. The crudereaction mixture was purified by reverse phase chromatography on C18column with gradient elution using CH₃CN and H₂O. Purification afforded222.2 mg (33% yield) of the desired product as a yellow oil; 1H NMR (700MHz, Chloroform-d) δ 6.22 (s, 1H), 5.85 (s, 1H), 5.26 (t, J=7.2 Hz, 1H),5.05 (t, J=6.8 Hz, 1H), 3.81-3.71 (m, 1H), 3.37 (d, J=7.1 Hz, 2H),2.15-2.03 (m, 4H), 1.88-1.79 (m, 4H), 1.67 (s, 3H), 1.59 (s, 3H), 1.41(dp, J=14.5, 7.3 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H), 0.91 (t, J=7.4 Hz,3H); 13C NMR (176 MHz, Chloroform-d) δ 210.80, 162.74, 161.00, 160.10,140.13, 132.30, 123.75, 121.62, 105.86, 104.86, 95.64, 46.07, 39.83,27.09, 26.44, 25.81, 21.76, 17.84, 16.82, 16.36, 12.09.

Synthesis of I-135

Prenol (100 mg, 1.16 mmol, 1 equiv.) and the acylphloroglucinolsubstrate (1.5 equiv.) were dissolved in EtOAc (0.2 M). Acidic alumina(2 g/mmol) was added to the reaction mixture and was allowed to stir atreflux for 24 h. The crude mixture was filtered over a Celite® pad,rinsed with EtOAc and concentrated to dryness under vacuum. The crudereaction mixture was purified by reverse phase chromatography on C18column with gradient elution using CH₃CN and H₂O. Purification afforded119.6 mg (35% yield) of the desired product as a yellow oil; 1H NMR (700MHz, Chloroform-d) δ 10.35 (s, 1H), 7.66-7.63 (m, 2H), 7.61-7.58 (m,1H), 7.52 (dd, J=8.4, 7.0 Hz, 2H), 7.37 (s, 1H), 6.02 (s, 1H), 5.94 (s,1H), 5.26 (tp, J=7.2, 1.4 Hz, 1H), 3.39-3.34 (m, 2H), 1.81 (d, J=1.4 Hz,3H), 1.76 (q, J=1.4 Hz, 3H); 13C NMR (176 MHz, Chloroform-d) δ 197.64,162.63, 160.83, 159.39, 139.90, 135.72, 132.33, 129.27, 127.85, 121.54,106.46, 104.58, 96.30, 25.84, 21.69, 17.91.

Synthesis of I-136

Geraniol (200 mg, 1.3 mmol, 1 equiv.) and the acylphloroglucinolsubstrate (1.5 equiv.) were dissolved in EtOAc (0.2 M). Acidic alumina(2 g/mmol) was added to the reaction mixture and was allowed to stir atreflux for 24 h. The crude mixture was filtered over a Celite® pad,rinsed with EtOAc and concentrated to dryness under vacuum. The crudereaction mixture was purified by reverse phase chromatography on C18column with gradient elution using CH₃CN and H₂O. Purification afforded148 mg (31% yield) of the desired product as a yellow oil; 1H NMR (700MHz, Chloroform-d) δ 10.37 (s, 1H), 7.65 (d, J=d, 8.1 Hz, 2H), 7.59 (t,J=7.4 Hz, 1H), 7.52 (dd, J=7.4, 8.1 Hz, 2H), 7.37 (br. s, 1H), 6.08 (br.s, 1H), 5.94 (s, 1H), 5.27 (t, J=7.2 Hz, 1H), 5.05 (t, J=7.0 Hz, 1H),3.38 (d, J=7.0 Hz, 2H), 2.10 (t, J=7.4 Hz, 2H), 2.07 (m, 2H), 1.80 (s,3H), 1.67 (s, 3H), 1.59 (s, 3H); 13C NMR (176 MHz, Chloroform-d) δ197.79, 163.00, 160.96, 159.53, 140.09, 139.76, 132.43, 129.37, 128.01,123.80, 121.56, 106.49, 96.52, 41.00, 39.85, 26.47, 25.82, 21.78, 17.86,16.37.

Synthesis of I-137

Isobutyrylphloroglucinol (200 mg, 1.02 mmol, 1 equiv.) and prenol (5equiv.) were dissolved in cyclohexane (0.2 M). Acidic alumina (2 g/mmol)was added to the reaction mixture and was allowed to stir at reflux for24 h. The crude mixture was filtered over a Celite® pad, rinsed withEtOAc and concentrated to dryness under vacuum. The crude reactionmixture was purified by reverse phase chromatography on C18 column withgradient elution using CH₃CN and H₂O. Purification afforded 159 mg (47%yield) of the desired product as a yellow oil; 1H NMR (700 MHz,Chloroform-d) δ 6.26 (s, 1H), 5.25-5.21 (m, 2H), 3.90 (h, J=6.7 Hz, 1H),3.38 (dd, J=7.5, 1.9 Hz, 4H), 1.84 (d, J=1.5 Hz, 6H), 1.79 (d, J=1.6 Hz,6H), 1.17 (d, J=6.7 Hz, 6H); 13C NMR (176 MHz, Chloroform-d) δ 210.97,159.12, 136.58, 121.69, 104.79, 104.39, 39.32, 25.87, 21.87, 19.41,17.92.

Synthesis of I-138: 4-Deoxyadhumulone

2′-methylisobutyrylphloroglucinol (200 mg, 0.95 mmol, 1 equiv.) andprenol (5 equiv.) were dissolved in cyclohexane (0.2 M). Acidic alumina(2 g/mmol) was added to the reaction mixture and was allowed to stir atreflux for 24 h. The crude mixture was filtered over a Celite® pad,rinsed with EtOAc and concentrated to dryness under vacuum. The crudereaction mixture was purified by reverse phase chromatography on C18column with gradient elution using CH₃CN and H₂O. Purification afforded102.8 mg (31% yield) of the desired product as a yellow oil; 1H NMR (700MHz, Chloroform-d) δ 6.26 (s, 1H), 5.23 (tp, J=7.2, 1.4 Hz, 2H), 3.76(h, J=6.7 Hz, 1H), 3.38 (d, J=7.2 Hz, 4H), 1.84 (d, J=1.4 Hz, 6H), 1.79(d, J=1.6 Hz, 6H), 1.47-1.33 (m, 2H), 1.15 (d, J=6.7 Hz, 3H), 0.90 (t,J=7.4 Hz, 3H).

Synthesis of I-139: Clusiaphenone B

Benzoylphloroglucinol (200 mg, 0.87 mmol, 1 equiv.) and prenol (5equiv.) were dissolved in cyclohexane (0.2 M). Acidic alumina (2 g/mmol)was added to the reaction mixture and was allowed to stir at reflux for24 h. The crude mixture was filtered over a Celite® pad, rinsed withEtOAc and concentrated to dryness under vacuum. The crude reactionmixture was purified by reverse phase chromatography on C18 column withgradient elution using CH₃CN and H₂O. Purification afforded 39.5 mg (12%yield) of the desired product as a yellow oil; 1H NMR (700 MHz,Chloroform-d) δ 8.91 (s, 2H), 7.64 (d, J=7.3 Hz, 2H), 7.57 (t, J=7.3 Hz,1H), 7.50 (t, J=7.7 Hz, 2H), 6.35 (s, 1H), 5.22 (t, J=7.1 Hz, 2H), 3.34(d, J=7.0 Hz, 4H), 1.79 (s, 6H), 1.74 (s, 6H); 13C NMR (176 MHz,Chloroform-d) δ 198.06, 161.10, 157.66, 140.30, 135.12, 132.07, 129.06,127.96, 121.85, 106.32, 104.56, 25.83, 21.85, 17.90.

Synthesis of I-140: Hyperbeanol Q

3-geranyl-1-benzoylphloroglucinol (150 mg, 0.41 mmol, 1 equiv.) andprenol (5 equiv.) were dissolved in cyclohexane (0.2 M). Acidic alumina(2 g/mmol) was added to the reaction mixture and was allowed to stir atreflux for 24 h. The crude mixture was filtered over a Celite® pad,rinsed with EtOAc and concentrated to dryness under vacuum. The crudereaction mixture was purified by reverse phase chromatography on C18column with gradient elution using CH₃CN and H2O. Purification afforded63.2 mg (36% yield) of the desired product as a yellow solid; 1H NMR(700 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.86 (s, 1H), 7.64 (d, J=7.4 Hz,2H), 7.58-7.55 (m, 1H), 7.49 (t, J=7.8 Hz, 2H), 6.36 (s, 1H), 5.22 (q,J=6.8, 6.3 Hz, 2H), 5.07-5.03 (m, 1H), 3.35 (dd, J=16.2, 7.1 Hz, 4H),2.10 (q, J=7.4 Hz, 2H), 2.07-2.03 (m, 2H), 1.78 (s, 6H), 1.73 (s, 3H),1.66 (s, 3H), 1.59 (s, 3H); 13C NMR (176 MHz, Chloroform-d) δ 198.14,161.11, 157.70, 157.67, 140.39, 139.12, 134.89, 132.03, 132.02, 128.97,127.99, 123.75, 121.90, 121.71, 106.45, 106.14, 104.58, 39.72, 26.36,25.83, 25.68, 21.84, 21.80, 17.89, 17.70, 16.22.

Synthesis of I-141

3-geranyl-1-isobutyrylphloroglucinol (150 mg, 0.45 mmol, 1 equiv.) andprenol (5 equiv.) were dissolved in cyclohexane (0.2 M). Acidic alumina(2 g/mmol) was added to the reaction mixture and was allowed to stir atreflux for 24 h. The crude mixture was filtered over a Celite® pad,rinsed with EtOAc and concentrated to dryness under vacuum. The crudereaction mixture was purified by reverse phase chromatography on C18column with gradient elution using CH₃CN and H2O. Purification afforded47.8 mg (26% yield) of the desired product as a yellow oil; 1H NMR (700MHz, Chloroform-d) δ 6.29 (s, 1H), 5.26-5.21 (m, 2H), 5.07-5.03 (m, 1H),3.90 (hept, J=6.7 Hz, 1H), 3.39 (t, J=7.6 Hz, 4H), 2.15-2.07 (m, 4H),1.84 (d, J=1.3 Hz, 3H), 1.83 (d, J=1.1 Hz, 3H), 1.79 (d, J=1.2 Hz, 3H),1.68 (d, J=1.4 Hz, 3H), 1.60 (d, J=1.6 Hz, 3H), 1.16 (d, J=6.7 Hz, 6H);13C NMR (176 MHz, Chloroform-d) δ 210.98, 159.22, 140.35, 136.53,132.24, 123.53, 121.73, 121.69, 104.84, 104.39, 39.69, 39.32, 26.22,25.87, 25.69, 21.86, 21.80, 19.41, 17.91, 17.72, 16.21.

Synthesis of I-142

3-geranyl-1-(2′-methylisobutyryl)phloroglucinol (200 mg, 0.60 mmol, 1equiv.) and prenol (5 equiv.) were dissolved in cyclohexane (0.2 M).Acidic alumina (2 g/mmol) was added to the reaction mixture and wasallowed to stir at reflux for 24 h. The crude mixture was filtered overa Celite® pad, rinsed with EtOAc and concentrated to dryness undervacuum. The crude reaction mixture was purified by reverse phasechromatography on C18 column with gradient elution using CH₃CN and H2O.Purification afforded 113.7 mg (43% yield) of the desired product as ayellow oil; 1H NMR (700 MHz, Chloroform-d) δ 6.29 (s, 1H), 5.27-5.20 (m,2H), 5.07-5.04 (m, 1H), 3.77 (h, J=6.7 Hz, 1H), 3.43-3.36 (m, 4H),2.16-2.07 (m, 4H), 1.86-1.82 (m, 6H), 1.80-1.78 (m, 3H), 1.70-1.66 (m,4H), 1.61-1.59 (m, 3H), 1.44-1.38 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 0.90(t, J=7.4 Hz, 3H).

Synthesis of I-143: 3-C-Prenylresacetophenone

To a stirring solution of 50 mg (0.58 mmol) of prenol (1 equiv.) and132.5 mg (0.87 mmol) of 2,4-dihydroxyacetophenone (1.5 equiv.) was added1161.8 mg of acidic alumina (2 g/mmol of prenol) in 3 mL of1,2-dichloroethane (0.2 M). The crude mixture was heated to 80° C. andstirred for 24 hours. The reaction was cooled down to room temperature,filtered through a Celite® pad and rinsed with EtOAc. The filtrate wasconcentrated under reduced pressure and purified by normal phasechromatography onto a 12 g SiO2 column, eluted from 2 to 20%EtOAc/hexanes over 20 CVs. 27.1 mg (21% yield) of the desired productwas recovered as a white solid; 1H NMR (400 MHz, Chloroform-d) δ 12.51(s, 1H), 7.44 (d, J=0.9 Hz, 1H), 6.36 (s, 1H), 5.71 (s, 1H), 5.29 (ddq,J=8.6, 5.8, 1.4 Hz, 1H), 3.31 (d, J=7.2 Hz, 2H), 2.55 (s, 3H), 1.79 (dt,J=2.7, 1.3 Hz, 6H).

Synthesis of I-144: Hispaglabridin A

To a stirring solution of 15 mg (0.17 mmol) of prenol (1 equiv.) and 226mg (0.70 mmol) of glabridin (4 equiv.) was added 348.6 mg of acidicalumina (2 g/mmol of prenol) in 1 mL of 1,2-dichloroethane (0.2 M). Thecrude mixture was heated to 80° C. and stirred for 24 hours. Thereaction was cooled down to room temperature, filtered through a Celite®pad and rinsed with EtOAc. The filtrate was concentrated under reducedpressure and purified by normal phase chromatography onto a 12 g SiO₂column, eluted in CH₂Cl₂ for 10 CVs, then gradient up to 10%EtOAc/CH₂Cl₂ over 10 CVs. 8.2 mg (12% yield) of the desired product wasrecovered as a yellow semi-solid; 1H NMR (400 MHz, Chloroform-d) δ 6.82(d, J=8.2 Hz, 1H), 6.79 (s, 1H), 6.65 (dd, J=9.8, 0.7 Hz, 1H), 6.37 (dd,J=8.2, 0.7 Hz, 1H), 6.29 (s, 1H), 5.56 (d, J=9.9 Hz, 1H), 5.28 (dddd,J=8.7, 5.8, 3.0, 1.5 Hz, 1H), 5.15 (s, 1H), 4.78 (s, 1H), 4.37 (ddd,J=10.4, 3.5, 2.1 Hz, 1H), 4.02 (t, J=10.3 Hz, 1H), 3.53-3.41 (m, 1H),3.26 (d, J=7.2 Hz, 2H), 2.99 (ddd, J=15.7, 11.1, 1.1 Hz, 1H), 2.85 (ddd,J=15.8, 5.2, 2.1 Hz, 1H), 1.76 (d, J=1.4 Hz, 6H), 1.42 (d, J=6.8 Hz,6H).

Synthesis of I-145: Dihydrochalcone M2

To a stirring solution of 175 mg (1.12 mmol) of geraniol (2 equiv.) and154 mg (0.56 mmol) of phloretin (1 equiv.) was added 2.19 g of acidicalumina (2 g/mmol of geraniol) in 3 mL of ethyl acetate. The mixture washeated to 77° C. and stirred for 24 hours. The reaction was cooled downto room temperature, filtered through a Celite® pad and rinsed withEtOAc and MeOH. The filtrate was concentrated under reduced pressure andpurified by normal phase chromatography with a gradient up to 60%EtOAc/Hex. 27.2 mg (12% yield) of the desired product was recovered as ayellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.03 (s, 1H), 10.54 (s, 1H),10.26 (s, 1H), 9.12 (br s, 1H), 7.01 (d, J=8.5 Hz, 2H), 6.66 (d, J=8.5Hz, 2H), 5.99 (s, 1H), 5.11 (5.11 (tt, J=5.8, 3.2 Hz, 1H), 5.03 (ddq,J=7.1, 5.4, 1.5 Hz, 1H), 3.21 (dd, J=8.6, 6.9 Hz, 2H), 3.08 (d, J=7.1Hz, 2H), 2.76 (dd, J=8.7, 6.8 Hz, 2H), 1.98 (dd, J=9.1, 5.6 Hz, 2H),1.88 (dd, J=9.0, 6.1 Hz, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

Synthesis of I-146

To a stirring solution of 34 mg (0.35 mmol) of prenol (2 equiv.) and 52mg (0.18 mmol) of biochanin (1 equiv.) was added 704 mg of acidicalumina (2 g/mmol of prenol) in 3 mL of 1,2 dichloroethane. The mixturewas heated to 80° C. and stirred for 24 hours. The reaction was cooleddown to room temperature, filtered through a Celite® pad and rinsed withEtOAc and MeOH. The filtrate was concentrated under reduced pressure andpurified by normal phase chromatography with a gradient up to 30%EtOAc/Hex. 17.3 mg (23% yield) of the desired product was recovered as awhite solid. 1H NMR (400 MHz, Chloroform-d) δ 13.18 (s, 1H), 7.91 (s,1H), 7.46 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.34 (s, 1H),5.39-5.08 (m, 2H), 3.84 (s, 3H), 3.49-3.45 (m, 4H), 1.84 (dd, J=4.6, 1.3Hz, 6H), 1.76 (dd, J=11.4, 1.5 Hz, 6H).

Synthesis of I-147: Demethylsuberosin

50 mg (2 equiv.) of umbelliferone (7-hydroxycoumarin) and 13.3 mg (1equiv.) of prenol (3-methyl-2-buten-1-ol) were suspended in drydichloroethane (DCE). 1.5 g/mmol of dry acidic alumina (Al₂O₃) relativeto the scaffold was added to the reaction mixture, which wassubsequently heated overnight at reflux. The mixture was then pouredover diatomaceous earth and washed with hexane, ethyl acetate, andacetone. The collected solvents were combined and concentrated underreduced pressure. Demethylsuberosin was eluted through columnchromatography using hexanes/ethyl acetate (13.3 mg, 37% yield). 1H NMR(400 MHz, Chloroform-d) δ 7.61 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 6.81 (s,1H), 6.23 (d, J=9.5 Hz, 1H), 6.08 (s, 1H), 5.34-5.27 (m, 1H), 3.38 (d,J=7.2 Hz, 2H), 1.87-1.70 (m, 6H).

Synthesis of I-148

4 equivalents of umbelliferone (7-hydroxycoumarin) and 1 equivalent ofprenol (3-methyl-2-buten-1-ol) were suspended in dry dichloroethane(DCE). 1.5 g/mmol of dry acidic alumina (Al₂O₃) relative to the scaffoldwas added to the reaction mixture, which was subsequently heatedovernight at reflux. The mixture was then poured over diatomaceous earthand washed with hexane, ethyl acetate, and acetone. The collectedsolvents were combined and concentrated under reduced pressure.7-hydroxy-8-(3-methylbut-2-en-1-yl)-2H-chromen-2-one was eluted throughcolumn chromatography using hexanes/ethyl acetate (14.2 mg, 40% yield).1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=9.5 Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.24 (d, J=9.5 Hz, 1H), 5.47 (ddq,J=8.1, 5.6, 1.4 Hz, 1H), 4.58 (dt, J=6.7, 0.9 Hz, 2H), 1.79 (dt, J=16.0,1.0 Hz, 6H).

Synthesis of I-149: Ostruthin

100 mg (2.1 equiv.) of umbelliferone (7-hydroxycoumarin) and 45 mg (1equiv.) of geraniol (3,7-dimethylocta-trans-2,6-dien-1-ol) weresuspended in xylenes. 1.5 g/mmol of dry acidic alumina (Al₂O₃) relativeto the scaffold was added to the reaction mixture, which wassubsequently heated at 160° C. for 2 hours in a monowave reactor. Themixture was then poured over diatomaceous earth and washed with hexane,ethyl acetate, and acetone. The collected solvents were combined andconcentrated under reduced pressure. Ostruthin was eluted through columnchromatography using hexanes/ethyl acetate (31.2 mg, 36% yield). 1H NMR(400 MHz, Chloroform-d) δ 7.61 (d, J=9.5 Hz, 1H), 7.19 (s, 1H), 6.84 (s,1H), 6.24 (d, J=9.4 Hz, 1H), 5.97 (s, 1H), 5.35-5.27 (m, 1H), 5.08(dddd, J=6.9, 5.5, 3.5, 1.7 Hz, 1H), 3.40 (d, J=7.2 Hz, 2H), 2.13 (q,J=5.3, 4.8 Hz, 4H), 1.77 (d, J=1.4 Hz, 3H), 1.69 (d, J=1.3 Hz, 3H), 1.61(d, J=1.3 Hz, 3H).

Synthesis of I-150: 8-geranylumbelliferone

100 mg (2.1 equiv.) of umbelliferone (7-hydroxycoumarin) and 45 mg (1equiv.) of geraniol (3,7-dimethylocta-trans-2,6-dien-1-ol) weresuspended in xylenes. 1.5 g/mmol of dry acidic alumina (Al₂O₃) relativeto the scaffold was added to the reaction mixture, which wassubsequently heated at 160° C. for 2 hours in a monowave reactor. Themixture was then poured over diatomaceous earth and washed with hexane,ethyl acetate, and acetone. The collected solvents were combined andconcentrated under reduced pressure. 8-geranylumbelliferone was elutedthrough column chromatography using hexanes/ethyl acetate (9.7 mg, 11%yield). 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=9.5 Hz, 1H), 7.24(d, J=8.4 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 6.24 (d, J=9.4 Hz, 1H), 6.20(s, 1H), 5.27 (tq, J=7.2, 1.3 Hz, 1H), 5.03 (dddt, J=6.8, 5.4, 2.8, 1.4Hz, 1H), 3.64 (d, J=7.3 Hz, 2H), 2.14-2.02 (m, 4H), 1.85 (q, J=1.0 Hz,3H), 1.66 (d, J=1.3 Hz, 3H), 1.58 (d, J=1.3 Hz, 3H).

Synthesis of I-151: 6-prenyl naringenin

48 mg (1.0 equiv.) of naringenin and 15 mg (1.0 equiv.) of prenol(3-methyl-2-buten-1-ol) were suspended in dichloroethane. 2.0 g/mmol ofdry acidic alumina (Al₂O₃) relative to the scaffold was added to thereaction mixture, which was subsequently heated at 120° C. for 2 hoursmonowave reactor. The mixture was then poured over diatomaceous earthand washed with ethyl acetate. The collected solvents were combined andconcentrated under reduced pressure. 6-prenylnaringenin was elutedthrough column chromatography on a C18 column using water/acetonitrile(0.1% trifluoroacetic acid) (3.6 mg, 6% yield). 1H NMR (400 MHz,Chloroform-d) δ 11.99 (s, 1H), 7.33 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 6.02 (s, 1H), 5.99 (s, 1H), 5.35 (dd, J=12.9, 3.0 Hz, 1H), 5.20(ddq, J=8.7, 5.7, 1.4 Hz, 1H), 3.31 (d, J=7.3 Hz, 2H), 3.05 (dd, J=17.1,13.0 Hz, 2H), 2.80 (dd, J=17.1, 3.0 Hz, 1H), 1.73 (s, J=1.3 Hz, 6H).

Synthesis of I-152: macarangin (6-geranyl kaempferol)

52 mg (1.0 equiv.) of kaempferol and 30 mg (1.0 equiv.) of geraniol(3,7-dimethylocta-trans-2,6-dien-1-ol) were suspended in dichloroethane.2.0 g/mmol of dry acidic alumina (Al₂O₃) relative to the scaffold wasadded to the reaction mixture, which was subsequently heated at 140° C.for 2 hours in a monowave reactor. The mixture was then poured overdiatomaceous earth and washed with ethyl acetate. The collected solventswere combined and concentrated under reduced pressure. Macarangin(6-geranylkaempferol was eluted through column chromatography on a C18column using water/acetonitrile (0.1% trifluoroacetic acid) (3.6 mg, 6%yield). 1H NMR (400 MHz, Chloroform-d) δ 11.73 (s, 1H), 8.13 (d, J=8.9Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 6.59 (s, 1H), 6.33 (s, 1H), 6.04 (s,1H), 5.31 (td, J=7.1, 1.3 Hz, 1H), 5.09 (s, 1H), 5.04 (dddd, J=8.1, 6.6,2.9, 1.4 Hz, 1H), 3.71 (s, 1H), 3.63 (d, J=7.1 Hz, 2H), 2.10 (m, 4H),1.86 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H).

Synthesis of I-153

25 mg (0.10 mmol, 1 equiv.) of 7-Hydroxyflavanone and 18 mg (0.21 mmol,2 equiv.) of (3-methyl-2-buten-1-ol) were suspended in dichloroethane.416 mg (2.0 g/mmol of prenol) of dry acidic alumina (Al₂O₃) was added tothe reaction mixture, which was subsequently heated at 150° C. for 20minutes in a monowave reactor. The mixture was cooled to roomtemperature and then poured over diatomaceous earth and washed withethyl acetate and methanol. The collected solvents were combined andconcentrated under reduced pressure. 6-prenyl-7-hydroxyflavanone waseluted through column chromatography using ethyl acetate/hexanes (1.7mg, 5% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J=1.2 Hz, 1H),7.59 (s, 1H), 7.51-7.34 (m, 5H), 5.51-5.39 (m, 1H), 5.36-5.27 (m, 1H),3.33 (dd, J=11.2, 6.6 Hz, 3H), 3.01 (dd, J=16.9, 13.0 Hz, 1H), 2.82 (dd,J=16.9, 3.0 Hz, 1H), 1.35 (d, J=2.2 Hz, 6H).

Synthesis of I-153

To a stirring solution of 39 mg (0.25 mmol) of geraniol (2 equiv.) and30 mg (0.13 mmol) of 7-Hydroxyflavanone (1 equiv.) was added 499.4 mg ofacidic alumina (2 g/mmol of geraniol) in 1.5 mL of 1,2 dichloroethane.The mixture was heated to 150° C. and stirred for 20 minutes. Thereaction was cooled down to room temperature, filtered through a Celitepad and rinsed with EtOAc and MeOH. The filtrate was concentrated underreduced pressure and purified by normal phase chromatography with agradient up to 25% EtOAc/Hex. 5.4 mg (11% yield) of the desired productwas recovered as a white solid. ¹H NMR (700 MHz, DMSO-d6) δ 9.40 (s,1H), 7.50 (s, 1H), 7.45-7.30 (m, 5H), 5.53 (dd, J=12.5, 3.1 Hz, 1H),5.11 (tt, J=7.0, 1.5 Hz, 1H), 5.02 (dddd, J=7.0, 5.6, 2.9, 1.5 Hz, 1H),3.24 (d, J=7.3 Hz, 2H), 3.01 (dd, J=16.7, 12.6 Hz, 1H), 2.75 (dd,J=16.7, 3.1 Hz, 1H), 1.98 (q, J=7.4 Hz, 2H), 1.89 (dd, J=9.0, 6.3 Hz,2H), 1.63 (s, 3H), 1.56 (s, 6H)

Synthesis of I-154

To a stirring solution of 25 mg (0.35 mmol) of prenol (1 equiv.) and 124mg (mmol) of biochanin (1.5 equiv.) was added 509 mg of acidic alumina(2 g/mmol of prenol) in 3 mL of 1,2 dichloroethane. The mixture washeated to 80° C. and stirred for 24 hours. The reaction was cooled downto room temperature, filtered through a Celite pad and rinsed with EtOAcand MeOH. The filtrate was concentrated under reduced pressure andpurified by normal phase chromatography with a gradient up to 25%EtOAc/Hex. 8.5 mg (8% yield) of the desired product was recovered as awhite solid. ¹H NM R (400 MHz, Chloroform-d) δ 12.85 (s, 1H), 7.92 (s,1H), 7.46 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 6.30 (s,z 1H), 5.24(mf, 1H), 3.84 (s, 3H), 3.51-3.44 (d, J=6.9 Hz, 2H), 1.83 (d, J=1.4 Hz,3H), 1.75 (d, J=1.6 Hz, 3H).

A person skilled in the art would appreciate that further manipulationof the substituent groups using known chemistry can be performed on theintermediates and final compounds in the Schemes above to providealternative compounds of the application.

Salts of compounds of the application may be formed by methods known tothose of ordinary skill in the art, for example, by reacting a compoundof the application with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or inaqueous medium followed by lyophilization.

The formation of solvates will vary depending on the compound and thesolvate. In general, solvates are formed by dissolving the compound inthe appropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions. The selection of suitable conditions to form a particularsolvate can be made by a person skilled in the art. Examples of suitablesolvents are ethanol, water and the like. When water is the solvent, themolecule is referred to as a “hydrate”. The formation of solvates of thecompounds of the application will vary depending on the compound and thesolvate. In general, solvates are formed by dissolving the compound inthe appropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions. The selection of suitable conditions to form a particularsolvate can be made by a person skilled in the art.

Throughout the processes described herein it is to be understood that,where appropriate, suitable protecting groups will be added to andsubsequently removed from, the various reactants and intermediates in amanner that will be readily understood by one skilled in the art.Conventional procedures for using such protecting groups as well asexamples of suitable protecting groups are described, for example, in“Protective Groups in Organic Synthesis”, T. W. Green, P. G. M. Wuts,Wiley-Interscience, New York, (1999). It is also to be understood that atransformation of a group or substituent into another group orsubstituent by chemical manipulation can be conducted on anyintermediate or final product on the synthetic path toward the finalproduct, in which the possible type of transformation is limited only byinherent incompatibility of other functionalities carried by themolecule at that stage to the conditions or reagents employed in thetransformation. Such inherent incompatibilities and ways to circumventthem by carrying out appropriate transformations and synthetic steps ina suitable order, will be readily understood to one skilled in the art.Examples of transformations are given herein and it is to be understoodthat the described transformations are not limited only to the genericgroups or substituents for which the transformations are exemplified.References and descriptions of other suitable transformations are givenin “Comprehensive Organic Transformations—A Guide to Functional GroupPreparations” R. C. Larock, VHC Publishers, Inc. (1989). References anddescriptions of other suitable reactions are described in textbooks oforganic chemistry, for example, “Advanced Organic Chemistry”, March, 4thed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill,(1994). Techniques for purification of intermediates and final productsinclude, for example, straight and reversed phase chromatography oncolumn or rotating plate, recrystallisation, distillation andliquid-liquid or solid-liquid extraction, which will be readilyunderstood by one skilled in the art.

While the present application has been described with reference toexamples, it is to be understood that the scope of the claims should notbe limited by the embodiments set forth in the examples, but should begiven the broadest interpretation consistent with the description as awhole.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. Where a term in the present application is found to bedefined differently in a document incorporated herein by reference, thedefinition provided herein is to serve as the definition for the term.

FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION

A number of publications are cited herein. Full citations for thesereferences are provided below. Each of these references is incorporatedherein by reference in its entirety into the present disclosure, to thesame extent as if each individual reference was specifically andindividually indicated to be incorporated by reference.

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1. A process for preparing a compound of Formula (I) comprising:

reacting a compound of Formula (II)

with a compound of Formula (III)

in the presence of an aluminum compound selected from alumina andaluminum alkoxides and in a non-protic solvent to form the compound ofFormula (I), wherein: n is 2, 3 or 4; two R¹ groups are linked togetherto form a polycyclic ring system having 8 or more atoms together withthe phenyl ring to which said groups are bonded, and in which one ormore carbon atoms in said polycyclic ring system is optionally replacedwith a heteromoiety selected from NR⁶, O and S, wherein the polycyclicring system is optionally substituted with one or more substituentsselected from ═O, OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl,OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸,C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups beingoptionally substituted with one or more substituents selected from OH,halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl; when n is 3 or 4,further R¹ groups are independently selected from OH, halo, CN, NO₂,COOH, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, C₃₋₁₈cycloalkyl,C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈ cycloalkyl,C₂₋₁₆alkynyleneC₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,C₁₋₁₆alkyleneC₃₋₁₈heterocycloalkyl,C₁₋₁₀alkenyleneC₃₋₁₈heterocycloalkyl,C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈ aryl, C₁₋₁₆alkyleneC₆₋₁₈aryl, C₂₋₁₆alkenyleneC₆₋₁₈ aryl, C₂₋₁₆alkynyleneC₆₋₁₈aryl,C₅₋₁₈heteroaryl, C₂₋₁₆alkyleneC₅₋₁₈heteroaryl,C₂₋₁₆alkenyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkynyleneC₅₋₁₈ heteroaryl,Z—C₂₋₁₆alkenyl, Z—C₂₋₁₆alkynyl, Z—C₃₋₁₈ cycloalkyl,Z—C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, Z—C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl,Z—C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl, Z—C₃₋₁₈heterocycloalkyl,Z—C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,Z—C₂₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl,Z—C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, Z—C₆₋₁₈aryl,Z—C₁₋₁₆alkyleneC₆₋₁₈aryl, Z—C₂₋₁₆alkenyleneC₆₋₁₈aryl,Z—C₂₋₁₆alkynyleneC₆₋₁₈aryl, Z—C₅₋₁₈heteroaryl, Z—C₁₋₁₆alkyleneC₅₋₁₈heteroaryl, Z—C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl, andZ—C₂₋₁₆alkynyleneC₅₋₁₈ heteroaryl, wherein all alkyl, alkenyl, alkynyl,alkylene, alkenylene, alkynylene, cycloalkyl heterocycloalkyl, aryl, andheteroaryl groups are optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, and OC₂₋₁₆alkynyl; Z isselected from O, C(O), CO₂, S, SO₂, SO, and NR⁷; R² is H, R³ is selectedfrom H and C₁₋₆alkyl, R⁴ is selected from H, C₁₋₆alkyl, C₆₋₁₈aryl,C₁₋₁₆alkyleneC₆₋₁₈aryl, C₅₋₁₈ heteroaryl, and C₂₋₁₆alkyleneC₅₋₁₈heteroaryl; R⁵ is selected from H, C₂₋₂₆alkenyl, C₂₋₂₆alkynyl, C₃₋₁₈cycloalkyl, C₁₋₁₆alkyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkenyleneC₃₋₁₈cycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,C₁₋₁₆alkyleneC₃₋₁₈ heterocycloalkyl,C₁₋₁₆alkenyleneC₃₋₁₈heterocycloalkyl, C₂₋₁₆alkynyleneC₃₋₁₈heterocycloalkyl, C₆₋₁₈aryl, C₁₋₁₆alkyleneC₆₋₁₈aryl,C₂₋₁₆alkenyleneC₆₋₁₈aryl, C₂₋₁₆alkynyleneC₆₋₁₈aryl, C₅₋₁₈heteroaryl,C₂₋₁₆alkyleneC₅₋₁₈heteroaryl, C₂₋₁₆alkenyleneC₅₋₁₈ heteroaryl,C₂₋₁₆alkynyleneC₅₋₁₈ heteroaryl, wherein all cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more substituents selected from OH, NO₂, CN, halo, C₁₋₁₆alkyl,C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁹ C₂₋₁₆alkenyleneOR⁹, C₂₋₁₆alkynyleneOR⁹, SO₃C₁₋₁₆alkyl,SO₃C₆₋₁₆aryl, and SO₃C₅₋₁₈heteroaryl substituted with C₁₋₁₆alkyl; or anytwo of R², R³, R⁴ and R⁵ are linked together to form an unsubstituted orsubstituted monocyclic or polycyclic ring system having 4 or more atomstogether with the carbon atoms to which said any two of R², R³, R⁴ andR⁵ are bonded, wherein the monocyclic or polycyclic ring system isoptionally substituted with one or more substituents selected ═O, OH,halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl; C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl; R⁶, R⁷, R⁸ and R⁹ are independentlyselected from H and C₁₋₆alkyl; and all alkyl, alkenyl, alkynyl,alkylene, alkenylene, alkynylene, cycloalkyl, and heterocycloalkylgroups are optionally fluoro-substituted.
 2. The process of claim 1,wherein the non-protic solvent is a non-polar solvent or a polar aproticsolvent.
 3. The process of claim 1, wherein the aluminum compound isacidic alumina.
 4. The process of claim 3, wherein the process furthercomprises a dehydrating agent and/or an acid.
 5. The process of claim 1,wherein the polycyclic ring system is a gonanyl (steroid nucleus) whichis optionally substituted with one or more substituents selected fromOH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 6. The process of claim 1, wherein thepolycyclic ring system is selected from benzofuranyl, isobenzofuranyl,indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzepinyl, carbazolyl,and acridinyl which are optionally substituted with one or moresubstituents selected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C(O)C₁₋₁₆alkyl,C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸,C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, and C₅₋₁₈heteroaryl, the latter 4 groups beingoptionally substituted with one or more substituents selected from OH,halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 7. The process of claim1, wherein the polycyclic ring system is a benzofused ring systemselected from benzofurochromenone, benzodiozinyl, benzodiozolyl,indenyl, indolinyl, chromenyl, dihydrochromenonyl, chromenonyl,chromanonyl, benzoxazinyl, quinolinonyl, isoquinolinonyl and coumarinylwhich are optionally substituted with one or more substituents selectedfrom OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 8. The process of claim 1, wherein thepolycyclic ring system is selected from chromenyl, chromenonyl(chromonyl) and chromanonyl (dihydrochromenonyl) which are optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl,C₃₋₁₈ cycloalkyl, C₃₋₁₈ heterocycloalkyl, and C₅₋₁₈heteroaryl, thelatter 4 groups being optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, andC₂₋₁₆alkenyl.
 9. The process of claim 1, wherein the polycyclic ringsystem is a flavonyl, isoflavonyl, flavavonyl or isoflavavonyl, whichare optionally substituted with one or more substituents selected fromOH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 10. The process ofclaim 1, wherein polycyclic ring system is coumarinyl which isoptionally substituted with one or more substituents selected from OH,═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl,OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C₂₋₁₆alkenyleneOR⁸,C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl, C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl,and C₅₋₁₈heteroaryl, the latter 4 groups being optionally substitutedwith one or more substituents selected from OH, halo, C₁₋₁₆alkyl,OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 11. The process of claim 1, wherein thepolycyclic ring system is selected from flourenyl, carbazolyl,dibenzofuranyl, phenoxazinyl, and xanthonyl which are optionallysubstituted with one or more substituents selected from OH, ═O, halo,C₁₋₁₆alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl,OC₂₋₁₆alkynyl, C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl,C(O)C₂₋₁₆alkynyl, C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈aryl,C₃₋₁₈cycloalkyl, C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heterocycloalkyl, thelatter 4 groups being optionally substituted with one or moresubstituents selected from OH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, andC₂₋₁₆alkenyl.
 12. The process of claim 1, wherein the polycyclic ringsystem is a benzofurochromenone which is optionally substituted with oneor more substituents selected from OH, C₁₋₁₆alkyl, C₂₋₁₆alkenyl, andOC₁₋₁₆alkyl.
 13. The process of claim 1, wherein the polycyclic ringsystem is selected from naphthalenyl, anthracenyl, phenanthrenyl,tetracenyl, chrysenyl, triphenylenyl, pyrenyl, pentacenyl,benzo[a]pyrenyl, corannulenyl, benzo[ghi]perylenyl, coronenyl, ovalenyland benzo[c]fluorinyl which are optionally substituted with one or moresubstituents selected from OH, ═O, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl,C₂₋₁₆alkynyl, OC₁₋₁₆alkyl, OC₂₋₁₆alkenyl, OC₂₋₁₆alkynyl,C₁₋₁₆alkyleneOR⁸, C(O)C₁₋₁₆alkyl, C(O)C₂₋₁₆alkenyl, C(O)C₂₋₁₆alkynyl,C₂₋₁₆alkenyleneOR⁸, C₂₋₁₆alkynyleneOR⁸, C₆₋₁₈ aryl, C₃₋₁₈ cycloalkyl,C₃₋₁₈heterocycloalkyl, and C₃₋₁₈heterocycloalkyl, the latter 4 groupsbeing optionally substituted with one or more substituents selected fromOH, halo, C₁₋₁₆alkyl, OC₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 14. The process ofclaim 1, when n is 3 or 4, further R¹ groups are independently selectedfrom OH, Br, Cl, F, C₁₋₁₂alkyl, C₂₋₁₆alkenyl, C₂₋₁₆alkynyl,0-C₁₋₁₂alkyl, C₁₋₁₆alkyleneOH, C(O)C₁₋₁₂alkyleneC₆₋₁₈ heterocycloalkyl,C(O)C₁₋₁₂alkenyleneC₃₋₁₈heterocycloalkyl, C(O)C₁₋₁₂alkyl,C(O)C₁₋₁₂alkyleneC₆₋₁₈ aryl, C(O)C₂₋₁₆alkenyleneC₆₋₁₈aryl, andC(O)C₆₋₁₈aryl wherein all alkyl, alkenyl, alkylene, alkenylene, alkynyl,heterocycloalkyl, and aryl groups are optionally substituted with one ormore substituents selected from OH, halo, C₁₋₁₆alkyl, C₂₋₁₆alkenyl andOC₁₋₁₆alkyl.
 15. The process of claim 1, wherein R³ is selected from H,CH₃ and CH₂CH₃.
 16. The process of claim 1, wherein R⁴ is selected fromH, CH₃, CH₂CH₃, C₆₋₁₀aryl, C₁₋₆alkyleneC₆₋₁₈ aryl, C₅₋₁₀heteroaryl, andC₂₋₆alkyleneC₅₋₁₀heteroaryl.
 17. The process of claim 1, wherein R⁵ isselected from H, C₁₋₁₀alkyl, C₂₋₂₀alkenyl, and C₆₋₁₀aryl, wherein arylis optionally substituted with one or more substituents selected fromOH, NO₂, CN, F, Cl, Br, C₁₋₆alkyl, C₂₋₁₆alkenyl, C₂₋₆alkynyl,OC₁₋₁₆alkyl and SO₃C₁₋₆alkyl.
 18. The process of claim 1, wherein R⁵ isselected from

wherein

represents a point of covalent attachment.
 19. The process of claim 1,wherein R² and R⁵ are linked together to form an unsubstituted orsubstituted monocyclic ring system having 6 or more atoms together withthe carbon atoms to which said R² and R⁵ are bonded, wherein themonocyclic ring system is optionally substituted with one or moresubstituents selected OH, C₁₋₁₆alkyl, and C₂₋₁₆alkenyl.
 20. The processof claim 1, wherein the compound of Formula (I) is a compound selectedfrom the compounds listed below: Compound I.D Structure I-10 

I-11 

I-23 

I-24 

I-25 

I-53 

I-54 

I-58 

I-59 

I-60 

I-61 

I-62 

I-63 

I-64 

I-65 

I-66 

I-67 

I-68 

I-69 

I-70 

I-71 

I-72 

I-73 

I-74 

I-75 

I-76 

I-77 

I-78 

I-79 

I-80 

I-81 

I-82 

I-83 

I-84 

I-85 

I-93 

I-94 

I-95 

I-96 

I-97 

I-98 

I-99 

I-100

I-101

I-102

I-117

I-118

I-119

I-120

I-121

I-122

I-129

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-159

I-162

I-164